The thalamus plays a pivotal role in the integration and processing of sensory, motor, and cognitive information. It is therefore important to understand how the thalamus operates in states of both health and disease. In the present review, we discuss the function of the Group II metabotropic glutamate (mGlu) receptors within thalamic circuitry, and how they may represent therapeutic targets in treating disease states associated with thalamic dysfunction.

The anatomically central position of the thalamus within the brain (Figure 1A) is functionally appropriate given its central role in the processing of almost all sensory, motor, and cognitive information: information entering the brain is first channelled to the relevant thalamic nuclei for processing and integration with other inputs prior to its subsequent dispatch to the corresponding cortical area(s). Consequentially, thalamic processing underpins the multimodal and multilevel functioning of the central nervous system (CNS) making it critical to understand how the thalamus operates. In recent years, there has been considerable work to understand how the Group II metabotropic glutamate (mGlu) receptors contribute to thalamic processing. Maintenance of the original spatiotemporal quality of stimuli through inhibition of top-down modulatory processes in the thalamus appears to be mediated by the Group II mGlu receptors, which have made them potential targets for therapeutic intervention to treat schizophrenia, pain, and epilepsy. In the present review, we describe the fundamentals of thalamic circuitry and Group II mGlu receptor pharmacology, how they interact, and their potential roles in health and disease.

Overview of Thalamic Nuclei

Figure 1
Overview of Thalamic Nuclei

(A) Location of the thalamus within the human brain. (B) Major nuclei comprising the thalamus. The thalamus in (A; red) has been enlarged in (B) to enable inspection of the major thalamic nuclei. Abbreviations: Ant, anterior; LD, dorsal lateral nucleus; LGN, lateral geniculate nucleus; LP, lateral posterior nucleus; MD, mediodorsal nucleus; MGN, medial geniculate nucleus; Pul, pulvinar; TRN, thalamic reticular nucleus; VA, ventral anterior nucleus; VL, ventral lateral nucleus; VP, ventral posterior nucleus; VPL, ventral posterolateral nucleus; VPM, ventral posteromedial nucleus. (A) reproduced under Creative Commons License CC BY-SA 2.1 JP.

Figure 1
Overview of Thalamic Nuclei

(A) Location of the thalamus within the human brain. (B) Major nuclei comprising the thalamus. The thalamus in (A; red) has been enlarged in (B) to enable inspection of the major thalamic nuclei. Abbreviations: Ant, anterior; LD, dorsal lateral nucleus; LGN, lateral geniculate nucleus; LP, lateral posterior nucleus; MD, mediodorsal nucleus; MGN, medial geniculate nucleus; Pul, pulvinar; TRN, thalamic reticular nucleus; VA, ventral anterior nucleus; VL, ventral lateral nucleus; VP, ventral posterior nucleus; VPL, ventral posterolateral nucleus; VPM, ventral posteromedial nucleus. (A) reproduced under Creative Commons License CC BY-SA 2.1 JP.

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The thalamus comprises over 30 distinct nuclei (Figure 1B) [1], with each nucleus governing the processing and relay of information to a discrete area of corresponding cerebral cortex. Information across all modalities, with the possible exception of olfaction, is relayed by thalamic neurons (sensory, motor, cognitive) [2,3]. These thalamic relay neurons receive information in two forms, namely driver inputs and modulatory inputs, which can be distinguished by their terminal morphology and synaptic location [3]: driver inputs have characteristic large round terminals that form synapses proximal to the soma of thalamic relay neurons, whereas modulatory inputs have small round terminals that form synapses distally onto the dendritic trees of thalamic relay neurons [3–6]. The source of information transmitted by driver inputs determines the classification of the thalamic nuclei they innervate as either first-order or higher-order nuclei, with first-order nuclei receiving and processing driver inputs from the periphery (e.g., visual, auditory, somatosensory), and higher-order nuclei receiving and processing driver inputs from cortical layer V [3–6] (note: some thalamic nuclei receive driver inputs from both the periphery and the cortex – for example, the posterior medial thalamus receives somatosensory driver inputs from both the periphery and cortical driver inputs from somatosensory, motor, perirhinal, and insular cortices [7–9] – such nuclei are considered mixed nuclei [10]).

A basic neuronal network, common to all thalamic nuclei, governs how driver inputs are relayed to the cortex [11–16] (Figure 2). Following innervation by a driver input, thalamic relay neurons send out an excitatory thalamocortical projection to layer IV of the cortex, and in return receive a reciprocal excitatory corticothalamic modulatory projection from cortical layer VI, which modulates how further driver inputs are processed prior to relay [3,5]. These thalamocortical and corticothalamic afferents also innervate the thalamic reticular nucleus (TRN), which in turn sends inhibitory modulatory projections back to the thalamic relay neuron from which it received its innervation (recurrent inhibition) and to surrounding thalamic relay neurons (lateral inhibition) [12,14–16]. The TRN is comprised exclusively of inhibitory neurons [17] and surrounds the entire anteroposterior extent of the dorsal thalamus (Figure 1B).

The basic neuronal network common to all thalamic nuclei

Figure 2
The basic neuronal network common to all thalamic nuclei

Each of the major thalamic nuclei in Figure 1B comprise the same basic circuitry. The source of driver inputs dictates the classification of thalamic nuclei as either a first- or higher-order nuclei, with first-order nuclei receiving and processing driver inputs from the periphery, and higher-order nuclei receiving and processing driver inputs from cortical layer V. Driver input – orange; thalamic relay neuron – blue; TRN – red; corticothalamic neuron – green. Abbreviation: TRN, thalamic reticular nucleus.

Figure 2
The basic neuronal network common to all thalamic nuclei

Each of the major thalamic nuclei in Figure 1B comprise the same basic circuitry. The source of driver inputs dictates the classification of thalamic nuclei as either a first- or higher-order nuclei, with first-order nuclei receiving and processing driver inputs from the periphery, and higher-order nuclei receiving and processing driver inputs from cortical layer V. Driver input – orange; thalamic relay neuron – blue; TRN – red; corticothalamic neuron – green. Abbreviation: TRN, thalamic reticular nucleus.

Close modal

Investigations of first-order nuclei have enabled the characterisation of this circuitry, as it is possible to physiologically activate sensory driver inputs with exacting fidelity [12,18,19]. This is particularly true for the rodent vibrissal system, which possesses a precise somatotopy with the arrangement of the whiskers of the snout reflected as discrete somatotopic maps in the brainstem as barrellettes, the ventrobasal thalamic nucleus (VB) as barreloids, and the somatosensory cortex as barrels (leading to this cortical region being sometimes referred to as barrel cortex) [20]. Furthermore, the rodent VB is devoid of any additional afferent projections or intrinsic inhibitory interneurons, which can be found in other rodent thalamic nuclei (e.g., the visual lateral geniculate nucleus [LGN]) and most thalamic nuclei of higher mammals such as primates [1,15,21–24]. This high degree of segregation and simplified organisation has therefore made the rodent VB a thalamic nucleus of choice for electrophysiologists to test and understand the basic neuronal network principles underpinning thalamic function.

Glutamate is the major excitatory neurotransmitter in the CNS and acts at both ionotropic glutamate and mGlu receptor types. Ionotropic glutamate receptor activation directly facilitates fast synaptic transmission, whilst the mGlu receptors provide a mechanism for glutamate to fine-tune synaptic activity [25]. Eight mGlu receptor subtypes (mGlu1–8) have been characterised, which have been classified into one of three groups (Groups I–III) dependent upon receptor sequence homology, signal transduction mechanism, and pharmacology [26].

Group II comprises the mGlu2 and mGlu3 receptor subtypes. These Group II mGlu receptors are often found on presynaptic terminals, which when activated ultimately lead to the inhibition of neurotransmitter release from the presynaptic terminal via their coupling to the Gi/o intracellular signalling cascade [27]. mGlu receptors native to physiological systems have been found to form obligatory functional dimers that greatly influence the efficiency with which these G-protein signalling cascades are activated [28,29]. These functional dimers take the form of homomeric complexes (i.e., mGlu2–mGlu2 and mGlu3–mGlu3 homodimers), but also heteromeric complexes with each other (i.e., mGlu2–mGlu3 heterodimers), other mGlu receptor subtypes (e.g., mGlu2–mGlu7 heterodimers) and receptors from other G-protein-coupled receptor families (e.g., mGlu2-5HT2A heterodimers) [28–34]. It is important to note however that a number of expression systems have been used to examine mGlu receptor signal transduction and are therefore not necessarily translatable to mGlu receptor signal transduction coupling across different cell types (e.g., neurons vs glia) [35,36].

The Group II mGlu receptor subtypes de facto have considerable sequence homology and therefore similar pharmacology [37]. Accordingly, there are a number of commercially available Group II mGlu receptor orthosteric agonists and antagonists, which orthosterically bind to both mGlu2 and mGlu3 receptor subtypes [38], but as of yet few that can differentiate between mGlu2 and mGlu3 receptors. LY2794193 has recently been developed as a selective mGlu3 receptor agonist [39], but has thus far had limited use in the scientific literature [40], and LY395756 is a compound with mixed properties that acts as an antagonist at mGlu2 receptors and an agonist at mGlu3 receptors [41]. This is an unusual pharmacology and as such experiments using LY395756 need careful interpretation [42–46] (note: N-acetylaspartateglutamate [NAAG] has been reported to selectively activate mGlu3 receptors [47], although this has not been confirmed in other studies [48] and there are questions regarding the purity of commercially available NAAG preparations [49]). There has been more success in the development of selective compounds, which target allosteric sites of the mGlu2 or mGlu3 receptors, namely positive and negative allosteric modulators (PAMs and NAMs) [50–56]. PAMs act to potentiate the response of a receptor to orthosteric agonists whilst possessing little or no intrinsic agonist activity, and NAMs antagonise the activity of agonists in a noncompetitive fashion by binding to a site distinct from the orthosteric-binding site [25].

The concept of allosteric modulation has received considerable attention in recent years, in part due to the clinical success of the anxiolytic benzodiazepines, which allosterically enhance the function of the ionotropic GABAA receptor [57], but also due to numerous advantages that this compound class has over exogenous orthosteric compounds. Firstly, orthosteric agonists activate their corresponding receptors independently of their physiological state, whereas PAMs act to enhance the action of receptors activated by endogenously released agonist. PAMs therefore increase physiological receptor activation with temporal and spatial relevance, and likely possess a lower side effect profile than orthosteric agonists. For example, the GABAB receptor PAMs CGP7930 and GS39783 [58,59] do not elicit the hypothermic, sedative, and muscle relaxant effects associated with the orthosteric agonist baclofen [60,61]. Secondly, PAMs are thought to induce either no or only low levels of receptor desensitisation, negating the consequence of receptor down-regulation that can occur upon persistent agonist treatment, as has been demonstrated for the GABAB receptor [62]. Finally, many PAMs are highly selective for a specific receptor, given the lack of necessity for allosteric binding sites to be conserved during evolution. This is in contrast with the requirement for the orthosteric site to be conserved for binding of endogenous agonist. However, it is important to consider that this also represents a potential disadvantage for the use of allosteric modulators in experimental design and interpretation. Indeed, although the low evolutionary conservation of allosteric sites facilitates subtype selectivity, it is important to consider that this may result in significant differences across species (e.g., rodents vs humans).

The mGlu2 receptor has a diffuse protein-staining pattern throughout the thalamus [63] with no significantly increased mRNA signal in any individual thalamic nucleus or the TRN [64]. There is some mGlu2 receptor localisation in cortical layer IV [64]; however, as there is an absence of mGlu2 (and mGlu3) receptor mRNA in thalamic relay neurons [64,65], this is unlikely to be due to presence of mGlu2 receptors on thalamocortical projections. This also indicates a lack of Group II mGlu receptors on thalamocortical projections to the TRN. In contrast, protein staining and mRNA analysis has revealed a highly localised expression of the mGlu3 receptor within the TRN, although little signal in the thalamus itself [64,66,67]. Double-labelling of Group II mGlu receptor protein and the GABAergic marker glutamic acid decarboxylase in the VB of mGlu2 deficient mice found considerable overlap [67], and as the VB lacks inhibitory interneurons [1,15,21–23], this indicates that the mGlu3 receptor is likely present at inhibitory GABAergic TRN terminals. In addition, immunogold particle labelling has also revealed that both mGlu2 and mGlu3 receptors can be found extrasynaptically [64,66,67]. Taken together, these results suggest that mGlu3 receptors are localised primarily on inhibitory TRN terminals that mGlu2 receptors are primarily on glutamatergic cortical terminals (although not thalamocortical in origin), and that both subtypes may be present on glial processes (Figure 3).

Locations of Group II mGlu receptors within thalamic nuclei

Figure 3
Locations of Group II mGlu receptors within thalamic nuclei

Whilst an astrocytic mGlu2 component has been demonstrated at synapse 1 (35), it remains to be evaluated whether there is an accompanying mGlu3 component. At synapses 2 and 3, the identity of the presynaptic Group II mGlu receptors mediating the relevant effects also remains to be delineated. Driver input – orange; thalamic relay neuron – blue; TRN – red; corticothalamic projection – green; astrocyte – yellow.

Figure 3
Locations of Group II mGlu receptors within thalamic nuclei

Whilst an astrocytic mGlu2 component has been demonstrated at synapse 1 (35), it remains to be evaluated whether there is an accompanying mGlu3 component. At synapses 2 and 3, the identity of the presynaptic Group II mGlu receptors mediating the relevant effects also remains to be delineated. Driver input – orange; thalamic relay neuron – blue; TRN – red; corticothalamic projection – green; astrocyte – yellow.

Close modal

Complementary physiological and pharmacological studies have provided substantial evidence that synaptically activated Group II mGlu receptors are present and functional at key synapses for information processing in the thalamus.

Synapse 1: the inhibitory modulatory input from the TRN to thalamic relay neurons

In vivo electrophysiology studies have demonstrated that Group II mGlu receptor activation with locally applied orthosteric agonists (e.g., 1S,3R-ACPD, L-CCG-I, 2R,4R-APDC) can reduce recurrent inhibition from the TRN to VB thalamic relay neurons upon somatosensory driver stimulation [68–71]. A later in vitro study complemented and extended these findings by showing that this Group II mGlu receptor activation with the orthosteric agonist LY354740 reduces inhibitory postsynaptic potential (IPSP) amplitude without affecting the postsynaptic cell membrane properties [72]. This indicates a pre- and/or extrasynaptic localisation of these receptors at the TRN-thalamic relay neuron synapse, which aligns with the findings of the ultrastructural cellular anatomy studies. This inhibitory role has also been shown in the first-order visual thalamic nucleus, the LGN [73], and the higher-order mediodorsal thalamic nucleus [74].

Following development of PAMs for the mGlu2 receptors, an mGlu2 component to this Group II mGlu receptor effect was revealed by local iontophoretic coapplication of the Group II mGlu receptor agonist LY354740 with the mGlu2 PAM LY487379 in vivo [75]. As ultrastructural studies indicate a lack of neuronal mGlu2 receptor expression in TRN or thalamic relay neurons, attention turned towards confirming the extrasynaptic localisation of these mGlu2 receptors on surrounding glial processes. In-vitro fluorescent calcium imaging in VB slices showed that increases in intracellular astrocytic calcium levels – but not intracellular neuronal calcium levels – could be induced upon application of the Group II mGlu receptor agonist LY354740, which could be further potentiated upon coapplication of the mGlu2 PAM LY487379 [35]. In vivo, the glial inhibitor fluorocitrate abolished the mGlu2 PAM LY487379 effect, whilst a considerable neuronal component of the Group II mGlu receptor agonist LY354740 effect was maintained. These data also support the ultrastructural studies (although an astrocytic mGlu3 receptor component remains to be confirmed). However, further in vitro and in vivo studies have brought into question the relative contribution that these astrocytic mGlu2 receptors make to the reduction in recurrent inhibition from the TRN to the thalamus. In vitro experiments in thalamic slices from mGlu3 knockout mice showed a complete ablation of the Group II mGlu receptor agonist LY354740 effect on IPSP amplitude, and use of the mixed mGlu2 receptor agonist/mGlu3 receptor antagonist compound LY395756 in vivo demonstrated a majority mGlu3 receptor component to the overall Group II mGlu receptor effect [45]: LY395756 is a more than sevenfold more potent mGlu2 receptor agonist (EC50 0.4 µM) than an mGlu3 receptor antagonist (IC50 2.94 µM) [41], yet the overriding effect of the mixed compound when applied alone was that of antagonism. Indeed, the mGlu2 receptor PAM LY487379 used to reveal the mGlu2 component in earlier studies is itself very effective as it can potentiate a ∼3% of maximal glutamate response (to 1 µM glutamate) up to ∼75% of maximal glutamate response [50] – a 2500% increase meaning that even low levels of mGlu2 receptor activation can be revealed. Therefore, the mGlu2 receptor effect revealed by the potent mGlu2 receptor PAM on reducing recurrent inhibition in the thalamus from the TRN may, under normal physiological conditions, minimally contribute to the overall Group II mGlu receptor effect. Indeed, in vivo experiments conducted in the higher-order mediodorsal thalamic nucleus showed that whilst the Group II mGlu receptor agonist LY354740 could reduce inhibition from the TRN upon prefrontal cortex and amygdala driver afferent stimulation, there was no potentiating effect upon coapplication of the mGlu2 receptor PAM LY487379 [74].

In addition to confirming the functional presence of the Group II mGlu receptors at the synapse from the TRN to thalamic relay neurons, these experiments also raise two important concepts. Firstly, they suggest that these Group II mGlu receptors are physiologically activated upon sensory stimulation: the mixed mGlu2 receptor agonist/mGlu3 receptor antagonist compound LY395756 was able to reduce thalamic relay neuron responses from baseline levels, indicating antagonism of endogenous receptor activation [45], and the mGlu2 PAM LY487379 was able to potentiate thalamic relay neuron responses in the absence of locally applied Group II mGlu receptor agonist LY354740 [75], also indicating endogenous receptor activation. The source of this endogenously released glutamate is likely to be from excitatory afferent terminals relaying either driver or modulatory information. Ultrastructural studies indicate that there are no axo-axonic contacts onto inhibitory TRN terminals, and corticothalamic modulatory afferent terminals are not closely associated with TRN terminals in the rat VB [76]. Therefore, transmission from and receptors associated with corticothalamic modulatory afferent terminals are unlikely to be involved in this mechanism. However, ultrastructural studies do indicate that driver afferent terminals are located close to inhibitory TRN afferent terminals and glial processes on the soma or proximal dendrites of thalamic relay neurons [21,76]. Glutamate may therefore be ‘spilling over’ from the driver afferent synapse to activate Group II mGlu receptors localised on glial processes surrounding TRN terminals [77,78] and/or mGlu3 receptors localized on TRN-originating inhibitory axons [67]. This could be leading to a reduction in recurrent inhibition with consequent facilitation of thalamic relay neuron responses to driver afferent stimulation. Similar ‘glutamate spillover’ has been shown to activate Group II mGlu receptors in vitro [73,79–82], making it appropriate to suggest that Group II mGlu receptors in the thalamus may be activated via this mechanism in vivo.

Secondly, as activation of the astrocytic mGlu2 receptors leads to an increase in intracellular calcium (Ca2+) concentration, this suggests mGlu2 receptor coupling to the Gq, rather than the more usual Gi/o, G-protein intracellular signal transduction cascade. It is possible that astrocytic mGlu2 receptors are directly coupled to the Gq intracellular signal transduction pathway as whilst normally associated with coupling to Gi/o G-proteins, there is evidence that mGlu receptors are able to couple to alternative G-proteins in different cell types [83,84]. It is also possible that astrocytic mGlu2 receptors are indirectly coupled to the Gq intracellular signal transduction pathway via receptor dimerisation, either with an mGlu receptor, which is traditionally associated with Gq intracellular signal transduction (e.g., the Group I mGlu receptors, mGlu1 and mGlu5 [25]), or a different class of G-protein-coupled receptor traditionally associated with Gq, such as 5HT2A receptors [32–34]. Further research is required to understand the intracellular signal cascade leading to increased intracellular Ca2+ concentration evoked upon astrocytic mGlu2 receptor activation.

Synapse 2: the excitatory input from corticothalamic projections to the TRN

In vitro electrophysiology experiments have indicated the presence of Group II mGlu receptors at both the pre- and postsynaptic sites of the corticothalamic-TRN synapse. Group II mGlu receptor agonists (LY379268, S3-C4HPG) were able to elicit hyperpolarisations and increase membrane conduction through potassium leak (Kleak) channels in TRN neurons [79,85]. This is likely mediated via postsynaptically located mGlu3 receptors as the TRN is devoid of mGlu2 receptor mRNA [64] and the effect persisted in the presence of tetrodotoxin [85]. The Group II mGlu receptor agonist LY379268 was also able to reduce the amplitude of the corticothalamic excitatory postsynaptic current (EPSC), which is likely mediated by presynaptic Group II mGlu receptors as a concurrent enhancement of the paired pulse facilitation ratio – a hallmark of presynaptic activity [86–88] – was observed [79]. The collective effects of this presynaptic inhibition of glutamate release and postsynaptic inhibition of TRN activity will be a disinhibition of thalamic relay neurons as inhibitory input from the TRN will be reduced. Both these pre- and postsynaptic Group II mGlu receptors are thought to be activated under physiologically relevant conditions by glutamate released from corticothalamic presynaptic terminals [79,89].

Synapse 3: the excitatory modulatory input from corticothalamic projections to thalamic relay neurons

The Group II mGlu receptor agonists LY379268 and DCG-IV were able to decrease corticothalamic EPSC amplitude, which is likely mediated by presynaptic Group II mGlu receptors as high-frequency trains produced a facilitating response that was reduced by the same Group II mGlu receptor agonists and enhanced by the Group II mGlu receptor antagonist LY341495 [73]. These presynaptic receptors are also thought to be activated under physiologically relevant conditions by glutamate released from the corticothalamic presynaptic terminal [73].

It is also worthy to note that Group II mGlu receptors can reduce innervation from inhibitory interneurons in the LGN [90]. There is, however, potentially contrasting evidence to this, which suggests that mGlu receptors can activate the dendritic terminals of inhibitory interneurons of the LGN in the absence of action potentials, thereby inhibiting postsynaptic LGN thalamic relay neurons [91]. However, the mGlu receptor subtypes mediating this effect have not yet been delineated. In addition, the Group II mGlu receptor agonist LY379268 was unable to perturb responses at the sensory driver afferent-thalamic relay neuron synapse in the LGN [73], in accordance with the lack of immunocytochemical evidence for Group II mGlu receptors at this synapse [64,65].

Collectively, the function of the Group II mGlu receptors at these synaptic locations is to reduce the top-down modulation of incoming information from driver afferents in a spatially and temporally specific manner: Group II mGlu receptors at synapses 1 and 2 decrease inhibitory modulation from the TRN, and those at synapse 3 decrease excitatory modulation from the cortex, with innervation from inhibitory interneurons also reduced by Group II mGlu receptor activation in thalamic nuclei, which contain these additional neuronal components.

The Group II mGlu receptors likely have physiologically relevant functions in the processing of information in the thalamus – functions, which when disrupted could lead to the generation of pathophysiological disease. Here, we discuss the potential roles of thalamic Group II mGlu receptors in states of health and disease.

Attention

The volume of information entering the brain far exceeds its processing power. Attentional mechanisms are therefore required for the prioritisation of important information. For example, think about the sensory information relayed to the brain in a crowded room – multiple visual and auditory inputs are entering the brain, but it is able to focus attention upon the person (and their voice) that you are talking to. This attentional selection is controlled through both ‘bottom-up’ and ‘top-down’ processes. Bottom-up attentional control is governed by the salience of a stimulus, and top-down modulation by previous experience and expectations [92]. In the thalamus, the synaptic interaction between the driver input, the thalamic relay neuron and the TRN terminal is an example of a bottom-up attentional process to promote sensory detection and discrimination: the firing rate of a thalamic relay neuron receiving a driver input would be relatively enhanced by the attenuation of recurrent – but not lateral – inhibition from the TRN. This selective attenuation can be achieved upon activation of Group II mGlu receptors on TRN terminals and surrounding glial processes (synapse 1) and on pre- and postsynaptic locations at the corticothalamic-TRN synapse (synapse 2). Such a mechanism would enable important information (such as a telephone ringing) to be discerned from background activity (such as a noisy crowd). This mechanism of sensory attention may represent an overarching principle of thalamic function to other first-order and higher-order thalamic nuclei given that mGlu3 receptors mediate the same attenuation of inhibition from the TRN in the higher-order cognitive thalamic nucleus, the mediodorsal thalamus [74].

In addition to bottom-up processes, top-down modulation of driver inputs also occurs in thalamic nuclei via innervation from corticothalamic afferents (synapse 3). Corticothalamic afferents are organised to provide feedback from the cortex that is functionally and spatially aligned with the thalamic relay neurons in order to mirror, and therefore amplify, their activity [93,94]. Such a mechanism would allow higher cortical areas to enhance the discriminative properties of thalamic relay neurons in a way that could increase the salience of responses to novel stimuli. At such synapses, the Group II mGlu receptors would act to preserve the original spatiotemporal quality of the driver input by reducing the mirroring of the corticothalamic innervation and subsequent amplification of thalamic relay neuron excitability.

Schizophrenia

Schizophrenia affects approximately 1% of the population and is characterized by three symptom profiles: (i) symptoms in addition to normal functioning, termed ‘positive’ symptoms (e.g., hallucinations, delusions); (ii) symptoms that represent an absence of normal functioning, termed ‘negative’ symptoms (e.g., anhedonia, poverty of speech); (iii) symptoms that affect cognitive function (e.g., impaired attention and working memory) [25]. Treatments for schizophrenia have focused on antagonism of the dopamine subtype 2 (D2) receptor [95]. However, it is becoming increasingly clear that dysfunction within the dopaminergic system is not sufficient to explain the pathophysiology of the disorder [96]. Indeed, therapies targeting this receptor subtype are often only efficacious in treating the positive symptoms of the disease (and only for a subgroup of patients), whilst exacerbating the negative and cognitive symptoms and inducing a plethora of side effects [95].

In recent years, there has been growing preclinical and clinical evidence for thalamic circuitry disruption in the pathophysiology of schizophrenia, particularly regarding the TRN [97–113]. As the TRN forms neuronal networks with thalamocortical and corticothalamic projections across all thalamic nuclei, TRN dysfunction would result in maladaptations across multiple modalities (e.g., sleep, emotional processing, cognitive performance) that rely on sensory processing and attention, and have been postulated to underlie the generation of hallucinations [100,105,107,114,115]. An emerging correlative theory of the pathophysiology of schizophrenia pertains to maintaining balance between excitatory and inhibitory signals within neuronal circuitries [116–118]. Disruptions of the excitatory–inhibitory balance in thalamic nuclei would have profound effects on how incoming information is processed and subsequently relayed in the thalamus as the usual firing patterns of thalamic relay neurons would be impacted: there are two types of firing patterns displayed by thalamic relay neurons – short-latency tonic responses, which occur at regular rates upon depolarization from resting potential and represent faithful relay of information through the thalamus, and long-latency burst responses that occur at irregular rates in hyperpolarised neurons and do not maintain the original spatiotemporal quality of the driver input [119–123]. Increased inhibition leading to hyperpolarised thalamic relay neurons and subsequent thalamic hypofunction has been associated with schizophrenia disease states in both animal models [124–127] and human imaging studies [128–132]. Reducing inhibition within thalamic nuclei to restore tonic-firing patterns and faithful relay of bottom-up driver inputs may therefore be of therapeutic benefit in the treatment of schizophrenia, such as that which can be achieved by activation of the Group II mGlu receptors to reduce inhibition from the TRN (synapses 1 and 2). Targeting of the mGlu3 receptor subtype specifically is likely of therapeutic importance as it is this Group II mGlu receptor subtype, which appears to majority mediate the effect of thalamic disinhibition in first- and higher-order circuitries [45,74]. Indeed, mGlu3 receptors have been implicated in the aetiological, pathophysiological, and pharmacotherapeutic aspects of schizophrenia [133–135], with polymorphisms in the mGlu3 receptor gene and protein, but not the mGlu2 receptor, detected in patients with schizophrenia [136–138]. mGlu3 PAMs have been identified as compounds of interest in the treatment of schizophrenia [135,139] and are proposed to have enhanced efficacy over direct Group II mGlu receptor agonists, which have had limited success [140–143]. However, no mGlu3 receptor PAMs are yet commercially available, although there are some in development [144].

Absence epilepsy

Absence epilepsy, which majority affects children [145], is characterised by a regular, bisynchronous, symmetrical, generalised EEG pattern of 2.5–5.5 Hz, which is termed a ‘spike-wave discharge’ [146]. Absence seizures typically manifest as a period of stillness, with the person appearing to stare blankly into space for a short period of time before returning to usual levels of alertness [145]. Whilst the origin of absence seizure activity remains to be determined [147–149], there is strong evidence to suggest thalamic involvement in their generation [150–152], and not just their maintenance and propagation. Current first-line therapies to treat absence epilepsy are typical anticonvulsants [95], which lack specificity due to their modulation of the GABAergic signalling [25]. The Group II mGlu receptors, which have distinct localisations in thalamic circuitry, have therefore been investigated as potential targets for the treatment of absence epilepsy.

The role of the Group II mGlu receptors in animal models of absence epilepsy is however highly debated as the Group II mGlu receptor agonist LY379268 has been found to reduce the duration of spike-wave discharges in a lethargic mouse model [153], but enhance spike-wave discharges in a WAG/Rij rat model [154]. These contrasting findings in two different rodent models of absence epilepsy are difficult to reconcile. Differential expression ratios of Group II mGlu receptor homo- and heterodimers [155] in the corticothalamic network underlying spike-wave discharges in lethargic mice and WAG/Rij rats two models has been cited as a potential explanation [156]. However, recent work with the selective mGlu3 receptor agonist LY2794193 in the WAG/Rij model suggests efficacy in reducing spike-wave discharges [40] in agreement with the lethargic mouse model findings but opposing the previous WAG/Rij findings. Alternatively, or indeed additionally, it is possible that this reflects species differences in Group II mGlu receptor signalling. Clearly, further work with subtype selective compounds is required to fully understand the role that each Group II mGlu receptor subtype plays in modulating spike-wave discharges in absence epilepsy, and it is likely that the effects of a systemically administered mGlu2-selective, mGlu3-selective, or mGlu2/3-pan-selective compound would reflect the relative differential distributions of mGlu2 and/or mGlu3 receptors within the corticothalamic network.

There is also growing evidence for modulation of epileptiform activity in the thalamus by the mGlu7 receptor subtype [157,158]. It is possible that heterodimeric mGlu2–mGlu7 receptor complexes are mediating some of these effects and as such should be considered in future investigations.

Arthritic pain

Arthritis manifests as swelling and inflammation in a joint, which can become painful. Osteoarthritis occurs when the cartilage lining the ends of bones becomes worn over time, with rheumatoid arthritis a result of an autoimmune disorder where the lining of joints is degraded [159].

mGlu3 receptor expression in the rat TRN can become elevated upon induction of arthritis [160]. As mGlu3 receptor activation can disinhibit thalamic relay neurons, mGlu3 receptor antagonism may be of use in the provision of analgesia in arthritic pain by reducing responsivity to nociceptive driver inputs. Indeed, when applied locally to the TRN, the Group II mGlu receptor antagonist EGLU had an antinociceptive effect in an arthritis pain model [161]. This was likely achieved via antagonism of mGlu3 receptors located: (i) pre- and postsynaptically at the corticothalamic-TRN synapse (synapse 2), which would increase TRN activity and therefore inhibition of somatosensory thalamic relay neurons, and (ii) at the TRN-thalamic relay neuron synapse (synapse 1), which would increase the inhibitory drive from TRN terminals.

The Group II mGlu receptors are located at key points in thalamic circuitry and likely contribute to the processing of incoming information prior to relay to the cortex. These roles in thalamic function represent potential targets for intervention in disease states including schizophrenia, epilepsy, and pain. Careful consideration is needed during the clinical development of mGlu2 and mGlu3 receptor PAMs to account for heterogeneity between rodent and human mGlu2 and mGlu3 receptor allosteric-binding sites as efficacy may not be translatable across species and act as a potential confounder. Furthermore, as compounds that act as orthosteric antagonists or NAMs at Group II mGlu receptors in other areas of the brain have been identified as potential therapies for other disorders (e.g., depression [82,162]), clinical developers of Group II mGlu receptor compounds need to be aware of the potential for the induction of unwanted side effects.

Data sharing is not applicable.

The authors declare that there are no competing interests associated with the manuscript.

Open access for the present article was enabled by the participation of University College London in an all-inclusive Read & Publish agreement with Portland Press and the Biochemical Society under a transformative agreement with JISC.

Caroline S. Copeland: Conceptualization, Writing—original draft, Writing—review & editing. Thomas E. Salt: Conceptualization, Writing—original draft, Writing—review & editing.

     
  • CNS

    central nervous system

  •  
  • EEG

    electroencephalogram

  •  
  • EGLU

    (2S)-α-ethylglutamic acid

  •  
  • EPSC

    excitatory postsynaptic current

  •  
  • IPSP

    inhibitory postsynaptic potential

  •  
  • LGN

    lateral geniculate nucleus

  •  
  • mGlu

    metabotropic glutamate

  •  
  • NAAG

    N-acetylaspartateglutamate

  •  
  • NAM

    negative allosteric modulator

  •  
  • PAM

    positive allosteric modulator

  •  
  • TRN

    thalamic reticular nucleus

  •  
  • VB

    ventrobasal

1.
Jones
E.G.
(
2007
)
The Thalamus
, 2nd edn,
Cambridge University Press
,
New York, USA
2.
Guillery
R.W.
and
Sherman
S.M.
(
2002
)
Thalamic relay functions and their role in corticocortical communication: generalizations from the visual system
.
Neuron
33
,
163
175
[PubMed]
3.
Sherman
S.M.
and
Guillery
R.W.
(
2011
)
Distinct functions for direct and transthalamic corticocortical connections
.
J. Neurophysiol.
106
,
1068
1077
[PubMed]
4.
Mitchell
A.S.
,
Sherman
S.M.
,
Sommer
M.A.
,
Mair
R.G.
,
Vertes
R.P.
and
Chudasama
Y.
(
2014
)
Advances in understanding mechanisms of thalamic relays in cognition and behavior
.
J. Neurosci.
34
,
15340
15346
[PubMed]
5.
Sherman
S.M.
(
2007
)
The thalamus is more than just a relay
.
Curr. Opin. Neurobiol.
17
,
417
422
[PubMed]
6.
Rovó
Z.
,
Ulbert
I.
and
Acsády
L.
(
2012
)
Drivers of the primate thalamus
.
J. Neurosci.
32
,
17894
17908
[PubMed]
7.
Hoogland
P.V.
,
Welker
E.
and
Van der Loos
H.
(
1987
)
Organization of the projections from barrel cortex to thalamus in mice studied with Phaseolus vulgaris-leucoagglutinin and HRP
.
Exp. Brain Res.
68
,
73
87
[PubMed]
8.
Deschênes
M.
,
Veinante
P.
and
Zhang
Z.W.
(
1998
)
The organization of corticothalamic projections: reciprocity versus parity
.
Brain Res. Brain Res. Rev.
28
,
286
308
[PubMed]
9.
Veinante
P.
,
Lavallée
P.
and
Deschênes
M.
(
2000
)
Corticothalamic projections from layer 5 of the vibrissal barrel cortex in the rat
.
J. Comp. Neurol.
424
,
197
204
[PubMed]
10.
Sherman
S.M.
and
Guillery
R.W.
(
2001
)
Exploring the Thalamus
,
Academic Press
,
New York
11.
Jones
E.G.
(
1985
)
The Thalamus
,
Raven
,
New York
12.
Salt
T.E.
(
1989
)
Gamma-aminobutyric acid and afferent inhibition in the cat and rat ventrobasal thalamus
.
Neuroscience
28
,
17
26
[PubMed]
13.
Shosaku
A.
,
Kayama
Y.
,
Sumitomo
I.
,
Sugitani
M.
and
Iwama
K.
(
1989
)
Analysis of recurrent inhibitory circuit in rat thalamus: neurophysiology of the thalamic reticular nucleus
.
Prog. Neurobiol.
32
,
77
102
[PubMed]
14.
Pinault
D.
and
Deschênes
M.
(
1998
)
Anatomical evidence for a mechanism of lateral inhibition in the rat thalamus
.
Eur. J. Neurosci.
10
,
3462
3469
[PubMed]
15.
Pinault
D.
and
Deschênes
M.
(
1998
)
Projection and innervation patterns of individual thalamic reticular axons in the thalamus of the adult rat: a three-dimensional, graphic, and morphometric analysis
.
J. Comp. Neurol.
391
,
180
203
[PubMed]
16.
Crabtree
J.W.
(
1999
)
Intrathalamic sensory connections mediated by the thalamic reticular nucleus
.
Cell. Mol. Life Sci.
56
,
683
700
[PubMed]
17.
Houser
C.R.
,
Vaughn
J.E.
,
Barber
R.P.
and
Roberts
E.
(
1980
)
GABA neurons are the major cell type of the nucleus reticularis thalami
.
Brain Res.
200
,
341
354
[PubMed]
18.
Weinberger
N.M.
and
Bakin
J.S.
(
1998
)
Learning-induced physiological memory in adult primary auditory cortex: receptive fields plasticity, model, and mechanisms
.
Audiol. Neurootol.
3
,
145
167
[PubMed]
19.
Wang
X.
,
Sommer
F.T.
and
Hirsch
J.A.
(
2011
)
Inhibitory circuits for visual processing in thalamus
.
Curr. Opin. Neurobiol.
21
,
726
733
[PubMed]
20.
Diamond
M.E.
,
von Heimendahl
M.
,
Knutsen
P.M.
,
Kleinfeld
D.
and
Ahissar
E.
(
2008
)
‘Where’ and ‘what’ in the whisker sensorimotor system
.
Nat. Rev. Neurosci.
9
,
601
612
[PubMed]
21.
Ralston
H.H.I.
(
1983
)
The synaptic organization of the ventrobasal thalamus in the rat, cat and monkey
.
Somatosensory Integration in the Thalamus
,
Elsevier Science
,
Amsterdam
22.
Harris
R.M.
and
Hendrickson
A.E.
(
1987
)
Local circuit neurons in the rat ventrobasal thalamus–a GABA immunocytochemical study
.
Neuroscience
21
,
229
236
[PubMed]
23.
Pinault
D.
(
1994
)
Golgi-like labeling of a single neuron recorded extracellularly
.
Neurosci. Lett.
170
,
255
260
[PubMed]
24.
Iavarone
E.
,
Yi
J.
,
Shi
Y.
,
Zandt
B.J.
,
O'Reilly
C.
,
Van Geit
W.
et al.
(
2019
)
Experimentally constrained biophysical models of tonic and burst firing modes in thalamocortical neurons
.
PLoS Comput. Biol.
15
,
e1006753
[PubMed]
25.
Ritter
J.
,
Flower
R.J.
,
Henderson
G.
,
MacEwan
D.J.
,
Loke
Y.K.
and
Rang
H.P.
(
2019
)
Rang and Dale's Pharmacology
, 9th edn,
Elsevier
,
Edinburgh
26.
Acher
F.C.
,
Cabayé
A.
,
Eshak
F.
,
Goupil-Lamy
A.
and
Pin
J.P.
(
2022
)
Metabotropic glutamate receptor orthosteric ligands and their binding sites
.
Neuropharmacology
204
,
108886
[PubMed]
27.
Kaneko
M.
and
Takahashi
T.
(
2004
)
Presynaptic mechanism underlying cAMP-dependent synaptic potentiation
.
J. Neurosci.
24
,
5202
5208
[PubMed]
28.
Levitz
J.
,
Habrian
C.
,
Bharill
S.
,
Fu
Z.
,
Vafabakhsh
R.
and
Isacoff
E.Y.
(
2016
)
Mechanism of assembly and cooperativity of homomeric and heteromeric metabotropic glutamate receptors
.
Neuron
92
,
143
159
[PubMed]
29.
Habrian
C.H.
,
Levitz
J.
,
Vyklicky
V.
,
Fu
Z.
,
Hoagland
A.
,
McCort-Tranchepain
I.
et al.
(
2019
)
Conformational pathway provides unique sensitivity to a synaptic mGluR
.
Nat. Commun.
10
,
5572
[PubMed]
30.
Du
J.
,
Wang
D.
,
Fan
H.
,
Xu
C.
,
Tai
L.
,
Lin
S.
et al.
(
2021
)
Structures of human mGlu2 and mGlu7 homo- and heterodimers
.
Nature
594
,
589
593
[PubMed]
31.
Meng
J.
,
Xu
C.
,
Lafon
P.A.
,
Roux
S.
,
Mathieu
M.
,
Zhou
R.
et al.
(
2022
)
Nanobody-based sensors reveal a high proportion of mGlu heterodimers in the brain
.
Nat. Chem. Biol.
18
,
894
903
[PubMed]
32.
González-Maeso
J.
,
Ang
R.L.
,
Yuen
T.
,
Chan
P.
,
Weisstaub
N.V.
,
López-Giménez
J.F.
et al.
(
2008
)
Identification of a serotonin/glutamate receptor complex implicated in psychosis
.
Nature
452
,
93
97
[PubMed]
33.
Moreno
J.L.
,
Miranda-Azpiazu
P.
,
García-Bea
A.
,
Younkin
J.
,
Cui
M.
,
Kozlenkov
A.
et al.
(
2016
)
Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia
.
Sci. Signal.
9
,
ra5
[PubMed]
34.
Toneatti
R.
,
Shin
J.M.
,
Shah
U.H.
,
Mayer
C.R.
,
Saunders
J.M.
,
Fribourg
M.
et al.
(
2020
)
Interclass GPCR heteromerization affects localization and trafficking
.
Sci. Signal.
13
,
eaaw3122
[PubMed]
35.
Copeland
C.S.
,
Wall
T.M.
,
Sims
R.E.
,
Neale
S.A.
,
Nisenbaum
E.
,
Parri
H.R.
et al.
(
2017
)
Astrocytes modulate thalamic sensory processing via mGlu2 receptor activation
.
Neuropharmacology
121
,
100
110
[PubMed]
36.
Conn
P.J.
and
Pin
J.P.
(
1997
)
Pharmacology and functions of metabotropic glutamate receptors
.
Annu. Rev. Pharmacol. Toxicol.
37
,
205
237
[PubMed]
37.
Pin
J.P.
and
Bockaert
J.
(
1995
)
Get receptive to metabotropic glutamate receptors
.
Curr. Opin. Neurobiol.
5
,
342
349
[PubMed]
38.
Nicoletti
F.
,
Bockaert
J.
,
Collingridge
G.L.
,
Conn
P.J.
,
Ferraguti
F.
,
Schoepp
D.D.
et al.
(
2011
)
Metabotropic glutamate receptors: from the workbench to the bedside
.
Neuropharmacology
60
,
1017
1041
[PubMed]
39.
Monn
J.A.
,
Henry
S.S.
,
Massey
S.M.
,
Clawson
D.K.
,
Chen
Q.
,
Diseroad
B.A.
et al.
(
2018
)
Synthesis and pharmacological characterization of C4(β)-amide-substituted 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1 S,2 S,4 S,5 R,6 S)-2-amino-4-[(3-methoxybenzoyl)amino]bicyclo [3.1.0]hexane-2,6-dicarboxylic acid (LY2794193), a highly potent and selective mGlu(3) receptor agonist
.
J. Med. Chem.
61
,
2303
2328
[PubMed]
40.
Celli
R.
,
Striano
P.
,
Citraro
R.
,
Di Menna
L.
,
Cannella
M.
,
Imbriglio
T.
et al.
(
2022
)
mGlu3 metabotropic glutamate receptors as a target for the treatment of absence epilepsy: preclinical and human genetics data
.
Curr. Neuropharmacol.
[PubMed]
41.
Dominguez
C.
,
Prieto
L.
,
Valli
M.J.
,
Massey
S.M.
,
Bures
M.
,
Wright
R.A.
et al.
(
2005
)
Methyl substitution of 2-aminobicyclo[3.1.0]hexane 2,6-dicarboxylate (LY354740) determines functional activity at metabotropic glutamate receptors: identification of a subtype selective mGlu2 receptor agonist
.
J. Med. Chem.
48
,
3605
3612
[PubMed]
42.
Lucas
S.J.
,
Bortolotto
Z.A.
,
Collingridge
G.L.
and
Lodge
D.
(
2013
)
Selective activation of either mGlu2 or mGlu3 receptors can induce LTD in the amygdala
.
Neuropharmacology
66
,
196
201
[PubMed]
43.
Li
M.L.
,
Yang
S.S.
,
Xing
B.
,
Ferguson
B.R.
,
Gulchina
Y.
,
Li
Y.C.
et al.
(
2015
)
LY395756, an mGluR2 agonist and mGluR3 antagonist, enhances NMDA receptor expression and function in the normal adult rat prefrontal cortex, but fails to improve working memory and reverse MK801-induced working memory impairment
.
Exp. Neurol.
273
,
190
201
[PubMed]
44.
Li
M.L.
,
Gulchina
Y.
,
Monaco
S.A.
,
Xing
B.
,
Ferguson
B.R.
,
Li
Y.C.
et al.
(
2017
)
Juvenile treatment with a novel mGluR2 agonist/mGluR3 antagonist compound, LY395756, reverses learning deficits and cognitive flexibility impairments in adults in a neurodevelopmental model of schizophrenia
.
Neurobiol. Learn. Mem.
140
,
52
61
[PubMed]
45.
Copeland
C.S.
,
Neale
S.A.
,
Nisenbaum
E.S.
and
Salt
T.E.
(
2022
)
Group II metabotropic glutamate receptor (mGlu(2) and mGlu(3)) roles in thalamic processing
.
Br. J. Pharmacol.
179
,
1607
1619
[PubMed]
46.
Li
M.L.
,
Peng
Y.
,
An
Y.
,
Li
G.Y.
and
Lan
Y.
(
2022
)
LY395756 promotes NR2B expression via activation of AKT/CREB signaling in the juvenile methylazoxymethanol mice model of schizophrenia
.
Brain Behav.
12
,
e2466
[PubMed]
47.
Wroblewska
B.
,
Wroblewski
J.T.
,
Pshenichkin
S.
,
Surin
A.
,
Sullivan
S.E.
and
Neale
J.H.
(
1997
)
N-acetylaspartylglutamate selectively activates mGluR3 receptors in transfected cells
.
J. Neurochem.
69
,
174
181
[PubMed]
48.
Fricker
A.C.
,
Mok
M.H.
,
de la Flor
R.
,
Shah
A.J.
,
Woolley
M.
,
Dawson
L.A.
et al.
(
2009
)
Effects of N-acetylaspartylglutamate (NAAG) at group II mGluRs and NMDAR
.
Neuropharmacology
56
,
1060
1067
[PubMed]
49.
Chopra
M.
,
Yao
Y.
,
Blake
T.J.
,
Hampson
D.R.
and
Johnson
E.C.
(
2009
)
The neuroactive peptide N-acetylaspartylglutamate is not an agonist at the metabotropic glutamate receptor subtype 3 of metabotropic glutamate receptor
.
J. Pharmacol. Exp. Ther.
330
,
212
219
[PubMed]
50.
Johnson
M.P.
,
Baez
M.
,
Jagdmann
G.E.
Jr.
,
Britton
T.C.
,
Large
T.H.
,
Callagaro
D.O.
et al.
(
2003
)
Discovery of allosteric potentiators for the metabotropic glutamate 2 receptor: synthesis and subtype selectivity of N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl) pyrid-3-ylmethylamine
.
J. Med. Chem.
46
,
3189
3192
[PubMed]
51.
Cid
J.M.
,
Tresadern
G.
,
Vega
J.A.
,
de Lucas
A.I.
,
Del Cerro
A.
,
Matesanz
E.
et al.
(
2016
)
Discovery of 8-trifluoromethyl-3-cyclopropylmethyl-7-[(4-(2,4-difluorophenyl)-1-piperazinyl)methyl]- 1,2,4-triazolo[4,3-a]pyridine (JNJ-46356479), a selective and orally bioavailable mGlu2 receptor positive allosteric modulator (PAM)
.
J. Med. Chem.
59
,
8495
8507
[PubMed]
52.
Griebel
G.
,
Pichat
P.
,
Boulay
D.
,
Naimoli
V.
,
Potestio
L.
,
Featherstone
R.
et al.
(
2016
)
The mGluR2 positive allosteric modulator, SAR218645, improves memory and attention deficits in translational models of cognitive symptoms associated with schizophrenia
.
Sci. Rep.
6
,
35320
[PubMed]
53.
Felts
A.S.
,
Rodriguez
A.L.
,
Smith
K.A.
,
Engers
J.L.
,
Morrison
R.D.
,
Byers
F.W.
et al.
(
2015
)
Design of 4-Oxo-1-aryl-1,4-dihydroquinoline-3-carboxamides as selective negative allosteric modulators of metabotropic glutamate receptor subtype 2
.
J. Med. Chem.
58
,
9027
9040
[PubMed]
54.
Bollinger
K.A.
,
Felts
A.S.
,
Brassard
C.J.
,
Engers
J.L.
,
Rodriguez
A.L.
,
Weiner
R.L.
et al.
(
2017
)
Design and synthesis of mGlu(2) NAMs with improved potency and CNS penetration based on a truncated picolinamide core
.
ACS Med. Chem. Lett.
8
,
919
924
[PubMed]
55.
Engers
J.L.
,
Rodriguez
A.L.
,
Konkol
L.C.
,
Morrison
R.D.
,
Thompson
A.D.
,
Byers
F.W.
et al.
(
2015
)
Discovery of a selective and CNS penetrant negative allosteric modulator of metabotropic glutamate receptor subtype 3 with antidepressant and anxiolytic activity in rodents
.
J. Med. Chem.
58
,
7485
7500
[PubMed]
56.
Engers
J.L.
,
Bollinger
K.A.
,
Weiner
R.L.
,
Rodriguez
A.L.
,
Long
M.F.
,
Breiner
M.M.
et al.
(
2017
)
Design and synthesis of N-aryl phenoxyethoxy pyridinones as highly selective and CNS penetrant mGlu(3) NAMs
.
ACS Med. Chem. Lett.
8
,
925
930
[PubMed]
57.
Sigel
E.
and
Buhr
A.
(
1997
)
The benzodiazepine binding site of GABAA receptors
.
Trends Pharmacol. Sci.
18
,
425
429
[PubMed]
58.
Urwyler
S.
,
Mosbacher
J.
,
Lingenhoehl
K.
,
Heid
J.
,
Hofstetter
K.
,
Froestl
W.
et al.
(
2001
)
Positive allosteric modulation of native and recombinant gamma-aminobutyric acid(B) receptors by 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and its aldehyde analog CGP13501
.
Mol. Pharmacol.
60
,
963
971
[PubMed]
59.
Urwyler
S.
,
Pozza
M.F.
,
Lingenhoehl
K.
,
Mosbacher
J.
,
Lampert
C.
,
Froestl
W.
et al.
(
2003
)
N,N'-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) and structurally related compounds: novel allosteric enhancers of gamma-aminobutyric acidB receptor function
.
J. Pharmacol. Exp. Ther.
307
,
322
330
[PubMed]
60.
Carai
M.A.
,
Colombo
G.
,
Froestl
W.
and
Gessa
G.L.
(
2004
)
In vivo effectiveness of CGP7930, a positive allosteric modulator of the GABAB receptor
.
Eur. J. Pharmacol.
504
,
213
216
[PubMed]
61.
Cryan
J.F.
,
Kelly
P.H.
,
Chaperon
F.
,
Gentsch
C.
,
Mombereau
C.
,
Lingenhoehl
K.
et al.
(
2004
)
Behavioral characterization of the novel GABAB receptor-positive modulator GS39783 (N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine): anxiolytic-like activity without side effects associated with baclofen or benzodiazepines
.
J. Pharmacol. Exp. Ther.
310
,
952
963
[PubMed]
62.
Gjoni
T.
and
Urwyler
S.
(
2008
)
Receptor activation involving positive allosteric modulation, unlike full agonism, does not result in GABAB receptor desensitization
.
Neuropharmacology
55
,
1293
1299
[PubMed]
63.
Neki
A.
,
Ohishi
H.
,
Kaneko
T.
,
Shigemoto
R.
,
Nakanishi
S.
and
Mizuno
N.
(
1996
)
Pre- and postsynaptic localization of a metabotropic glutamate receptor, mGluR2, in the rat brain: an immunohistochemical study with a monoclonal antibody
.
Neurosci. Lett.
202
,
197
200
[PubMed]
64.
Ohishi
H.
,
Shigemoto
R.
,
Nakanishi
S.
and
Mizuno
N.
(
1993
)
Distribution of the messenger RNA for a metabotropic glutamate receptor, mGluR2, in the central nervous system of the rat
.
Neuroscience
53
,
1009
1018
[PubMed]
65.
Ohishi
H.
,
Shigemoto
R.
,
Nakanishi
S.
and
Mizuno
N.
(
1993
)
Distribution of the mRNA for a metabotropic glutamate receptor (mGluR3) in the rat brain: an in situ hybridization study
.
J. Comp. Neurol.
335
,
252
266
[PubMed]
66.
Lourenço Neto
F.
,
Schadrack
J.
,
Berthele
A.
,
Zieglgänsberger
W.
,
Tölle
T.R.
and
Castro-Lopes
J.M.
(
2000
)
Differential distribution of metabotropic glutamate receptor subtype mRNAs in the thalamus of the rat
.
Brain Res.
854
,
93
105
[PubMed]
67.
Tamaru
Y.
,
Nomura
S.
,
Mizuno
N.
and
Shigemoto
R.
(
2001
)
Distribution of metabotropic glutamate receptor mGluR3 in the mouse CNS: differential location relative to pre- and postsynaptic sites
.
Neuroscience
106
,
481
503
[PubMed]
68.
Salt
T.E.
and
Eaton
S.A.
(
1995
)
Modulation of sensory neurone excitatory and inhibitory responses in the ventrobasal thalamus by activation of metabotropic excitatory amino acid receptors
.
Neuropharmacology
34
,
1043
1051
[PubMed]
69.
Salt
T.E.
and
Eaton
S.A.
(
1995
)
Distinct presynaptic metabotropic receptors for L-AP4 and CCG1 on GABAergic terminals: pharmacological evidence using novel alpha-methyl derivative mGluR antagonists, MAP4 and MCCG, in the rat thalamus in vivo
.
Neuroscience
65
,
5
13
[PubMed]
70.
Salt
T.E.
and
Eaton
S.A.
(
1996
)
Functions of ionotropic and metabotropic glutamate receptors in sensory transmission in the mammalian thalamus
.
Prog. Neurobiol.
48
,
55
72
[PubMed]
71.
Salt
T.E.
and
Turner
J.P.
(
1998
)
Modulation of sensory inhibition in the ventrobasal thalamus via activation of group II metabotropic glutamate receptors by 2R,4R-aminopyrrolidine-2,4-dicarboxylate
.
Exp. Brain Res.
121
,
181
185
[PubMed]
72.
Turner
J.P.
and
Salt
T.E.
(
2003
)
Group II and III metabotropic glutamate receptors and the control of the nucleus reticularis thalami input to rat thalamocortical neurones in vitro
.
Neuroscience
122
,
459
469
[PubMed]
73.
Alexander
G.M.
and
Godwin
D.W.
(
2005
)
Presynaptic inhibition of corticothalamic feedback by metabotropic glutamate receptors
.
J. Neurophysiol.
94
,
163
175
[PubMed]
74.
Copeland
C.S.
,
Neale
S.A.
and
Salt
T.E.
(
2015
)
Neuronal activity patterns in the mediodorsal thalamus and related cognitive circuits are modulated by metabotropic glutamate receptors
.
Neuropharmacology
92
,
16
24
[PubMed]
75.
Copeland
C.S.
,
Neale
S.A.
and
Salt
T.E.
(
2012
)
Positive allosteric modulation reveals a specific role for mGlu2 receptors in sensory processing in the thalamus
.
J. Physiol.
590
,
937
951
[PubMed]
76.
Ohara
P.T.
and
Lieberman
A.R.
(
1993
)
Some aspects of the synaptic circuitry underlying inhibition in the ventrobasal thalamus
.
J. Neurocytol.
22
,
815
825
[PubMed]
77.
Mineff
E.
and
Valtschanoff
J.
(
1999
)
Metabotropic glutamate receptors 2 and 3 expressed by astrocytes in rat ventrobasal thalamus
.
Neurosci. Lett.
270
,
95
98
[PubMed]
78.
Liu
X.B.
,
Muñoz
A.
and
Jones
E.G.
(
1998
)
Changes in subcellular localization of metabotropic glutamate receptor subtypes during postnatal development of mouse thalamus
.
J. Comp. Neurol.
395
,
450
465
[PubMed]
79.
Alexander
G.M.
and
Godwin
D.W.
(
2006
)
Unique presynaptic and postsynaptic roles of Group II metabotropic glutamate receptors in the modulation of thalamic network activity
.
Neuroscience
141
,
501
513
[PubMed]
80.
Linden
A.M.
,
Bergeron
M.
and
Schoepp
D.D.
(
2005
)
Comparison of c-Fos induction in the brain by the mGlu2/3 receptor antagonist LY341495 and agonist LY354740: evidence for widespread endogenous tone at brain mGlu2/3 receptors in vivo
.
Neuropharmacology
49
,
120
134
[PubMed]
81.
Chen
C.Y.
and
Bonham
A.C.
(
2005
)
Glutamate suppresses GABA release via presynaptic metabotropic glutamate receptors at baroreceptor neurones in rats
.
J. Physiol.
562
,
535
551
[PubMed]
82.
Joffe
M.E.
,
Santiago
C.I.
,
Oliver
K.H.
,
Maksymetz
J.
,
Harris
N.A.
,
Engers
J.L.
et al.
(
2020
)
mGlu(2) and mGlu(3) negative allosteric modulators divergently enhance thalamocortical transmission and exert rapid antidepressant-like effects
.
Neuron
105
,
46.e3
59.e3
[PubMed]
83.
Kang
H.J.
,
Menlove
K.
,
Ma
J.
,
Wilkins
A.
,
Lichtarge
O.
and
Wensel
T.G.
(
2014
)
Selectivity and evolutionary divergence of metabotropic glutamate receptors for endogenous ligands and G proteins coupled to phospholipase C or TRP channels
.
J. Biol. Chem.
289
,
29961
29974
[PubMed]
84.
Nasrallah
C.
,
Rottier
K.
,
Marcellin
R.
,
Compan
V.
,
Font
J.
,
Llebaria
A.
et al.
(
2018
)
Direct coupling of detergent purified human mGlu(5) receptor to the heterotrimeric G proteins Gq and Gs
.
Sci. Rep.
8
,
4407
[PubMed]
85.
Cox
C.L.
and
Sherman
S.M.
(
1999
)
Glutamate inhibits thalamic reticular neurons
.
J. Neurosci.
19
,
6694
6699
[PubMed]
86.
Shigemoto
R.
,
Kinoshita
A.
,
Wada
E.
,
Nomura
S.
,
Ohishi
H.
,
Takada
M.
et al.
(
1997
)
Differential presynaptic localization of metabotropic glutamate receptor subtypes in the rat hippocampus
.
J. Neurosci.
17
,
7503
7522
[PubMed]
87.
Zucker
R.S.
and
Regehr
W.G.
(
2002
)
Short-term synaptic plasticity
.
Annu. Rev. Physiol.
64
,
355
405
[PubMed]
88.
Granseth
B.
,
Ahlstrand
E.
and
Lindström
S.
(
2002
)
Paired pulse facilitation of corticogeniculate EPSCs in the dorsal lateral geniculate nucleus of the rat investigated in vitro
.
J. Physiol.
544
,
477
486
[PubMed]
89.
Crabtree
J.W.
,
Lodge
D.
,
Bashir
Z.I.
and
Isaac
J.T.
(
2013
)
GABAA NMDA and mGlu2 receptors tonically regulate inhibition and excitation in the thalamic reticular nucleus
.
Eur. J. Neurosci.
37
,
850
859
[PubMed]
90.
Govindaiah
G.
and
Cox
C.L.
(
2006
)
Metabotropic glutamate receptors differentially regulate GABAergic inhibition in thalamus
.
J. Neurosci.
26
,
13443
13453
[PubMed]
91.
Cox
C.L.
,
Zhou
Q.
and
Sherman
S.M.
(
1998
)
Glutamate locally activates dendritic outputs of thalamic interneurons
.
Nature
394
,
478
482
[PubMed]
92.
Crabtree
J.W.
(
2018
)
Functional diversity of thalamic reticular subnetworks
.
Front. Syst. Neurosci.
12
,
41
93.
Wang
W.
,
Jones
H.E.
,
Andolina
I.M.
,
Salt
T.E.
and
Sillito
A.M.
(
2006
)
Functional alignment of feedback effects from visual cortex to thalamus
.
Nat. Neurosci.
9
,
1330
1336
[PubMed]
94.
Jones
H.E.
,
Andolina
I.M.
,
Ahmed
B.
,
Shipp
S.D.
,
Clements
J.T.
,
Grieve
K.L.
et al.
(
2012
)
Differential feedback modulation of center and surround mechanisms in parvocellular cells in the visual thalamus
.
J. Neurosci.
32
,
15946
15951
[PubMed]
95.
Katzung
B.B.
,
Masters
S.B.
and
Trevor
A.J.
(
2019
)
Basic & Clinical Pharmacology
, 12th edn,
McGraw Hill
,
Lange
96.
McCutcheon
R.A.
,
Krystal
J.H.
and
Howes
O.D.
(
2020
)
Dopamine and glutamate in schizophrenia: biology, symptoms and treatment
.
World Psychiatry
19
,
15
33
[PubMed]
97.
Anticevic
A.
,
Yang
G.
,
Savic
A.
,
Murray
J.D.
,
Cole
M.W.
,
Repovs
G.
et al.
(
2014
)
Mediodorsal and visual thalamic connectivity differ in schizophrenia and bipolar disorder with and without psychosis history
.
Schizophr. Bull.
40
,
1227
1243
[PubMed]
98.
Anticevic
A.
,
Haut
K.
,
Murray
J.D.
,
Repovs
G.
,
Yang
G.J.
,
Diehl
C.
et al.
(
2015
)
Association of thalamic dysconnectivity and conversion to psychosis in youth and young adults at elevated clinical risk
.
JAMA Psychiatry
72
,
882
891
[PubMed]
99.
Marenco
S.
,
Stein
J.L.
,
Savostyanova
A.A.
,
Sambataro
F.
,
Tan
H.Y.
,
Goldman
A.L.
et al.
(
2012
)
Investigation of anatomical thalamo-cortical connectivity and FMRI activation in schizophrenia
.
Neuropsychopharmacology
37
,
499
507
[PubMed]
100.
Shenton
M.E.
,
Dickey
C.C.
,
Frumin
M.
and
McCarley
R.W.
(
2001
)
A review of MRI findings in schizophrenia
.
Schizophr. Res.
49
,
1
52
[PubMed]
101.
Klingner
C.M.
,
Langbein
K.
,
Dietzek
M.
,
Smesny
S.
,
Witte
O.W.
,
Sauer
H.
et al.
(
2014
)
Thalamocortical connectivity during resting state in schizophrenia
.
Eur. Arch. Psychiatry Clin. Neurosci.
264
,
111
119
[PubMed]
102.
Anticevic
A.
,
Cole
M.W.
,
Repovs
G.
,
Murray
J.D.
,
Brumbaugh
M.S.
,
Winkler
A.M.
et al.
(
2014
)
Characterizing thalamo-cortical disturbances in schizophrenia and bipolar illness
.
Cereb. Cortex
24
,
3116
3130
[PubMed]
103.
Anticevic
A.
,
Repovs
G.
,
Krystal
J.H.
and
Barch
D.M.
(
2012
)
A broken filter: prefrontal functional connectivity abnormalities in schizophrenia during working memory interference
.
Schizophr. Res.
141
,
8
14
[PubMed]
104.
Welsh
R.C.
,
Chen
A.C.
and
Taylor
S.F.
(
2010
)
Low-frequency BOLD fluctuations demonstrate altered thalamocortical connectivity in schizophrenia
.
Schizophr. Bull.
36
,
713
722
[PubMed]
105.
Woodward
N.D.
,
Karbasforoushan
H.
and
Heckers
S.
(
2012
)
Thalamocortical dysconnectivity in schizophrenia
.
Am. J. Psychiatry
169
,
1092
1099
[PubMed]
106.
Zhang
J.
,
Chu
K.W.
,
Teague
E.B.
,
Newmark
R.E.
and
Buchsbaum
M.S.
(
2013
)
fMRI assessment of thalamocortical connectivity during attentional performance
.
Magn. Reson. Imaging
31
,
1112
1118
[PubMed]
107.
Shinn
A.K.
,
Baker
J.T.
,
Cohen
B.M.
and
Ongür
D.
(
2013
)
Functional connectivity of left Heschl's gyrus in vulnerability to auditory hallucinations in schizophrenia
.
Schizophr. Res.
143
,
260
268
[PubMed]
108.
Steullet
P.
,
Cabungcal
J.H.
,
Bukhari
S.A.
,
Ardelt
M.I.
,
Pantazopoulos
H.
,
Hamati
F.
et al.
(
2018
)
The thalamic reticular nucleus in schizophrenia and bipolar disorder: role of parvalbumin-expressing neuron networks and oxidative stress
.
Mol. Psychiatry
23
,
2057
2065
[PubMed]
109.
Behrens
M.M.
,
Ali
S.S.
,
Dao
D.N.
,
Lucero
J.
,
Shekhtman
G.
,
Quick
K.L.
et al.
(
2007
)
Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase
.
Science
318
,
1645
1647
[PubMed]
110.
Czekus
C.
,
Steullet
P.
,
Orero López
A.
,
Bozic
I.
,
Rusterholz
T.
,
Bandarabadi
M.
et al.
(
2022
)
Alterations in TRN-anterodorsal thalamocortical circuits affect sleep architecture and homeostatic processes in oxidative stress vulnerable Gclm(-/-) mice
.
Mol. Psychiatry
[PubMed]
111.
El Khoueiry
C.
,
Cabungcal
J.H.
,
Rovó
Z.
,
Fournier
M.
,
Do
K.Q.
and
Steullet
P.
(
2022
)
Developmental oxidative stress leads to T-type Ca(2+) channel hypofunction in thalamic reticular nucleus of mouse models pertinent to schizophrenia
.
Mol. Psychiatry
27
,
2042
2051
[PubMed]
112.
Zhu
X.
,
Cabungcal
J.H.
,
Cuenod
M.
,
Uliana
D.L.
,
Do
K.Q.
and
Grace
A.A.
(
2021
)
Thalamic reticular nucleus impairments and abnormal prefrontal control of dopamine system in a developmental model of schizophrenia: prevention by N-acetylcysteine
.
Mol. Psychiatry
26
,
7679
7689
[PubMed]
113.
You
Q.L.
,
Luo
Z.C.
,
Luo
Z.Y.
,
Kong
Y.
,
Li
Z.L.
,
Yang
J.M.
et al.
(
2021
)
Involvement of the thalamic reticular nucleus in prepulse inhibition of acoustic startle
.
Transl. Psychiatry
11
,
241
[PubMed]
114.
Behrendt
R.P.
(
2006
)
Dysregulation of thalamic sensory “transmission” in schizophrenia: neurochemical vulnerability to hallucinations
.
J. Psychopharmacol.
20
,
356
372
[PubMed]
115.
Walther
S.
and
Strik
W.
(
2012
)
Motor symptoms and schizophrenia
.
Neuropsychobiology
66
,
77
92
[PubMed]
116.
Liu
Y.
,
Ouyang
P.
,
Zheng
Y.
,
Mi
L.
,
Zhao
J.
,
Ning
Y.
et al.
(
2021
)
A selective review of the excitatory-inhibitory imbalance in schizophrenia: underlying biology, genetics, microcircuits, and symptoms
.
Front. Cell Dev. Biol.
9
,
664535
[PubMed]
117.
Lisman
J.
(
2012
)
Excitation, inhibition, local oscillations, or large-scale loops: what causes the symptoms of schizophrenia?
Curr. Opin. Neurobiol.
22
,
537
544
[PubMed]
118.
Yizhar
O.
,
Fenno
L.E.
,
Prigge
M.
,
Schneider
F.
,
Davidson
T.J.
,
O'Shea
D.J.
et al.
(
2011
)
Neocortical excitation/inhibition balance in information processing and social dysfunction
.
Nature
477
,
171
178
[PubMed]
119.
Fernandez de Molina
A.
and
Ispizua
A.
(
1972
)
Neuronal activity evoked in nucleus medialis dorsalis of the thalamus after stimulation of the amygdala
.
Physiol. Behav.
8
,
135
138
[PubMed]
120.
Llinás
R.
and
Jahnsen
H.
(
1982
)
Electrophysiology of mammalian thalamic neurones in vitro
.
Nature
297
,
406
408
[PubMed]
121.
Jahnsen
H.
and
Llinás
R.
(
1984
)
Electrophysiological properties of guinea-pig thalamic neurones: an in vitro study
.
J. Physiol.
349
,
205
226
[PubMed]
122.
Ramcharan
E.J.
,
Gnadt
J.W.
and
Sherman
S.M.
(
2000
)
Burst and tonic firing in thalamic cells of unanesthetized, behaving monkeys
.
Vis. Neurosci.
17
,
55
62
[PubMed]
123.
Rivadulla
C.
,
Martinez
L.
,
Grieve
K.L.
and
Cudeiro
J.
(
2003
)
Receptive field structure of burst and tonic firing in feline lateral geniculate nucleus
.
J. Physiol.
553
,
601
610
[PubMed]
124.
Parnaudeau
S.
,
O'Neill
P.K.
,
Bolkan
S.S.
,
Ward
R.D.
,
Abbas
A.I.
,
Roth
B.L.
et al.
(
2013
)
Inhibition of mediodorsal thalamus disrupts thalamofrontal connectivity and cognition
.
Neuron
77
,
1151
1162
[PubMed]
125.
Benoit
L.J.
,
Holt
E.S.
,
Posani
L.
,
Fusi
S.
,
Harris
A.Z.
,
Canetta
S.
et al.
(
2022
)
Adolescent thalamic inhibition leads to long-lasting impairments in prefrontal cortex function
.
Nat. Neurosci.
25
,
714
725
[PubMed]
126.
Karimi
B.
,
Silwal
P.
,
Booth
S.
,
Padmanabhan
N.
,
Dhume
S.H.
,
Zhang
D.
et al.
(
2021
)
Schizophrenia-associated LRRTM1 regulates cognitive behavior through controlling synaptic function in the mediodorsal thalamus
.
Mol. Psychiatry
26
,
6912
6925
[PubMed]
127.
Francoeur
M.J.
,
Wormwood
B.A.
,
Gibson
B.M.
and
Mair
R.G.
(
2019
)
Central thalamic inactivation impairs the expression of action- and outcome-related responses of medial prefrontal cortex neurons in the rat
.
Eur. J. Neurosci.
50
,
1779
1798
[PubMed]
128.
Csukly
G.
,
Szabó
Á.
,
Polgár
P.
,
Farkas
K.
,
Gyebnár
G.
,
Kozák
L.R.
et al.
(
2020
)
Fronto-thalamic structural and effective connectivity and delusions in schizophrenia: a combined DTI/DCM study
.
Psychol. Med.
51
,
1
11
[PubMed]
129.
Wu
G.
,
Palaniyappan
L.
,
Zhang
M.
,
Yang
J.
,
Xi
C.
,
Liu
Z.
et al.
(
2022
)
Imbalance between prefronto-thalamic and sensorimotor-thalamic circuitries associated with working memory deficit in schizophrenia
.
Schizophr. Bull.
48
,
251
261
[PubMed]
130.
Xi
C.
,
Liu
Z.N.
,
Yang
J.
,
Zhang
W.
,
Deng
M.J.
,
Pan
Y.Z.
et al.
(
2020
)
Schizophrenia patients and their healthy siblings share decreased prefronto-thalamic connectivity but not increased sensorimotor-thalamic connectivity
.
Schizophr. Res.
222
,
354
361
[PubMed]
131.
Chen
P.
,
Ye
E.
,
Jin
X.
,
Zhu
Y.
and
Wang
L.
(
2019
)
Association between thalamocortical functional connectivity abnormalities and cognitive deficits in schizophrenia
.
Sci. Rep.
9
,
2952
[PubMed]
132.
Giraldo-Chica
M.
,
Rogers
B.P.
,
Damon
S.M.
,
Landman
B.A.
and
Woodward
N.D.
(
2018
)
Prefrontal-thalamic anatomical connectivity and executive cognitive function in schizophrenia
.
Biol. Psychiatry
83
,
509
517
[PubMed]
133.
Harrison
P.J.
,
Lyon
L.
,
Sartorius
L.J.
,
Burnet
P.W.J.
and
Lane
T.A.
(
2008
)
Review: the group II metabotropic glutamate receptor 3 (mGluR3, mGlu3, GRM3): expression, function and involvement in schizophrenia
.
J. Psychopharmacol.
22
,
308
322
[PubMed]
134.
Dogra
S.
,
Stansley
B.J.
,
Xiang
Z.
,
Qian
W.
,
Gogliotti
R.G.
,
Nicoletti
F.
et al.
(
2021
)
Activating mGlu(3) metabotropic glutamate receptors rescues schizophrenia-like cognitive deficits through metaplastic adaptations within the hippocampus
.
Biol. Psychiatry
90
,
385
398
[PubMed]
135.
Dogra
S.
and
Conn
P.J.
(
2022
)
Metabotropic glutamate receptors as emerging targets for the treatment of schizophrenia
.
Mol. Pharmacol.
101
,
275
285
[PubMed]
136.
Ghose
S.
,
Gleason
K.A.
,
Potts
B.W.
,
Lewis-Amezcua
K.
and
Tamminga
C.A.
(
2009
)
Differential expression of metabotropic glutamate receptors 2 and 3 in schizophrenia: a mechanism for antipsychotic drug action?
Am. J. Psychiatry
166
,
812
820
[PubMed]
137.
Cherlyn
S.Y.
,
Woon
P.S.
,
Liu
J.J.
,
Ong
W.Y.
,
Tsai
G.C.
and
Sim
K.
(
2010
)
Genetic association studies of glutamate, GABA and related genes in schizophrenia and bipolar disorder: a decade of advance
.
Neurosci. Biobehav. Rev.
34
,
958
977
[PubMed]
138.
Mounce
J.
,
Luo
L.
,
Caprihan
A.
,
Liu
J.
,
Perrone-Bizzozero
N.I.
and
Calhoun
V.D.
(
2014
)
Association of GRM3 polymorphism with white matter integrity in schizophrenia
.
Schizophr. Res.
155
,
8
14
[PubMed]
139.
Mazzitelli
M.
and
Neugebauer
V.
(
2021
)
mGlu(3) metabotropic glutamate receptors-new hope for pharmacotherapy of schizophrenia
.
Biol. Psychiatry
90
,
356
358
[PubMed]
140.
Stauffer
V.L.
,
Millen
B.A.
,
Andersen
S.
,
Kinon
B.J.
,
Lagrandeur
L.
,
Lindenmayer
J.P.
et al.
(
2013
)
Pomaglumetad methionil: no significant difference as an adjunctive treatment for patients with prominent negative symptoms of schizophrenia compared to placebo
.
Schizophr. Res.
150
,
434
441
[PubMed]
141.
Adams
D.H.
,
Kinon
B.J.
,
Baygani
S.
,
Millen
B.A.
,
Velona
I.
,
Kollack-Walker
S.
et al.
(
2013
)
A long-term, phase 2, multicenter, randomized, open-label, comparative safety study of pomaglumetad methionil (LY2140023 monohydrate) versus atypical antipsychotic standard of care in patients with schizophrenia
.
BMC Psychiatry
13
,
143
[PubMed]
142.
Kinon
B.J.
,
Zhang
L.
,
Millen
B.A.
,
Osuntokun
O.O.
,
Williams
J.E.
,
Kollack-Walker
S.
et al.
(
2011
)
A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia
.
J. Clin. Psychopharmacol.
31
,
349
355
[PubMed]
143.
Patil
S.T.
,
Zhang
L.
,
Martenyi
F.
,
Lowe
S.L.
,
Jackson
K.A.
,
Andreev
B.V.
et al.
(
2007
)
Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial
.
Nat. Med.
13
,
1102
1107
[PubMed]
144.
Pharmaceuticals A
(
2022
)
mGlu3 PAM for neurodegenerative disorders
.
145.
Scheffer
I.E.
,
Berkovic
S.
,
Capovilla
G.
,
Connolly
M.B.
,
French
J.
,
Guilhoto
L.
et al.
(
2017
)
ILAE classification of the epilepsies: position paper of the ILAE Commission for classification and terminology
.
Epilepsia
58
,
512
521
[PubMed]
146.
Akman
O.
,
Demiralp
T.
,
Ates
N.
and
Onat
F.Y.
(
2010
)
Electroencephalographic differences between WAG/Rij and GAERS rat models of absence epilepsy
.
Epilepsy Res.
89
,
185
193
[PubMed]
147.
Depaulis
A.
and
Charpier
S.
(
2018
)
Pathophysiology of absence epilepsy: Insights from genetic models
.
Neurosci. Lett.
667
,
53
65
[PubMed]
148.
Holmes
M.D.
,
Brown
M.
and
Tucker
D.M.
(
2004
)
Are “generalized” seizures truly generalized? Evidence of localized mesial frontal and frontopolar discharges in absence
Epilepsia
45
,
1568
1579
[PubMed]
149.
Paz
J.T.
and
Huguenard
J.R.
(
2015
)
Microcircuits and their interactions in epilepsy: is the focus out of focus?
Nat. Neurosci.
18
,
351
359
[PubMed]
150.
Avoli
M.
(
2012
)
A brief history on the oscillating roles of thalamus and cortex in absence seizures
.
Epilepsia
53
,
779
789
[PubMed]
151.
Meeren
H.
,
van Luijtelaar
G.
,
Lopes da Silva
F.
and
Coenen
A.
(
2005
)
Evolving concepts on the pathophysiology of absence seizures: the cortical focus theory
.
Arch. Neurol.
62
,
371
376
[PubMed]
152.
Niedermeyer
E.
(
1996
)
Primary (idiopathic) generalized epilepsy and underlying mechanisms
.
Clin. Electroencephalogr.
27
,
1
21
[PubMed]
153.
Moldrich
R.X.
,
Jeffrey
M.
,
Talebi
A.
,
Beart
P.M.
,
Chapman
A.G.
and
Meldrum
B.S.
(
2001
)
Anti-epileptic activity of group II metabotropic glutamate receptor agonists (–)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268) and (–)-2-thia-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY389795)
.
Neuropharmacology
41
,
8
18
[PubMed]
154.
Ngomba
R.T.
,
Biagioni
F.
,
Casciato
S.
,
Willems-van Bree
E.
,
Battaglia
G.
,
Bruno
V.
et al.
(
2005
)
The preferential mGlu2/3 receptor antagonist, LY341495, reduces the frequency of spike-wave discharges in the WAG/Rij rat model of absence epilepsy
.
Neuropharmacology
49
,
89
103
[PubMed]
155.
Di Menna
L.
,
Joffe
M.E.
,
Iacovelli
L.
,
Orlando
R.
,
Lindsley
C.W.
,
Mairesse
J.
et al.
(
2018
)
Functional partnership between mGlu3 and mGlu5 metabotropic glutamate receptors in the central nervous system
.
Neuropharmacology
128
,
301
313
[PubMed]
156.
Celli
R.
,
Santolini
I.
,
Van Luijtelaar
G.
,
Ngomba
R.T.
,
Bruno
V.
and
Nicoletti
F.
(
2019
)
Targeting metabotropic glutamate receptors in the treatment of epilepsy: rationale and current status
.
Expert Opin. Ther. Targets
23
,
341
351
[PubMed]
157.
Tassin
V.
,
Girard
B.
,
Chotte
A.
,
Fontanaud
P.
,
Rigault
D.
,
Kalinichev
M.
et al.
(
2016
)
Phasic and tonic mGlu7 receptor activity modulates the thalamocortical network
.
Front. Neural. Circuits
10
,
31
[PubMed]
158.
Girard
B.
,
Tuduri
P.
,
Moreno
M.P.
,
Sakkaki
S.
,
Barboux
C.
,
Bouschet
T.
et al.
(
2019
)
The mGlu7 receptor provides protective effects against epileptogenesis and epileptic seizures
.
Neurobiol. Dis.
129
,
13
28
[PubMed]
159.
Mohammed
A.
,
Alshamarri
T.
,
Adeyeye
T.
,
Lazariu
V.
,
McNutt
L.A.
and
Carpenter
D.O.
(
2020
)
A comparison of risk factors for osteo- and rheumatoid arthritis using NHANES data
.
Prev. Med. Rep.
20
,
101242
[PubMed]
160.
Lourenço Neto
F.
,
Schadrack
J.
,
Platzer
S.
,
Zieglgänsberger
W.
,
Tölle
T.R.
and
Castro-Lopes
J.M.
(
2000
)
Expression of metabotropic glutamate receptors mRNA in the thalamus and brainstem of monoarthritic rats
.
Brain Res. Mol. Brain Res.
81
,
140
154
[PubMed]
161.
Neto
F.L.
and
Castro-Lopes
J.M.
(
2000
)
Antinociceptive effect of a group II metabotropic glutamate receptor antagonist in the thalamus of monoarthritic rats
.
Neurosci. Lett.
296
,
25
28
[PubMed]
162.
Chaki
S.
and
Fukumoto
K.
(
2018
)
mGlu receptors as potential targets for novel antidepressants
.
Curr. Opin. Pharmacol.
38
,
24
30
[PubMed]
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