Neuroscience is a rapidly developing area of science which has benefitted from the blurring of interdisciplinary boundaries. This was apparent in the range of papers presented at this year's Neuroscience Ireland Conference, held in Galway during August 2008. The event was attended by academics, postdoctoral and postgraduate researchers, scientists from industry and clinicians. The themes of this year's conference, neurodegeneration, neuroregeneration, pain, glial cell biology and psychopharmacology, were chosen for their reflection of areas of strength in neuroscience within Ireland. In addition to basic science, translational research also featured strongly.

Neurodegeneration and neuroregeneration

Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and ischaemia, are characterized by the loss or dysfunction of subsets of neurons. The important issues in developing therapies for these diseases are to understand the mechanisms of neuronal cell death and of loss of neuronal function in order to develop neuroprotective therapies to prevent loss of functional neurons. Failing that, it is important to develop cell replacement strategies to restore function.

Although many neurodegenerative diseases are associated with genetic mutations [such as familial Alzheimer's disease, familial Parkinson's disease, ALS (amyotrophic lateral sclerosis) and Huntington's disease], in the vast majority of patients, there is no obvious genetic linkage and the cause of the disease is unknown and may involve environmental factors. Notably, one factor that is positively correlated with an increased risk of developing neurodegenerative disease is an increase in age. This suggests that some age-related factor contributes to the deterioration in neuronal function, e.g. accumulation of neuronal stresses. On pp. xxx–xxx, Alessia Piazza and Marina Lynch explore one of the major factors associated with aging, namely neuroinflammation and how it relates to neurodegeneration and loss of synaptic function [1]. The main culprit in neuroinflammation is the activation of microglial cells which are the primary source of pro-inflammatory cytokines such as IL (interleukin)-1β. For many years Lynch and co-workers have been investigating the observation that neuroinflammation is common to several neurodegenerative diseases [2]. In their paper, they report on the evidence that neuroinflammation is a feature of Alzheimer's disease, specifically that there is increased expression of IL-1β and of microglial activation [1]. In fact, IL-1β-positive microglia are found clustered around amyloid plaques. Other markers of activated microglia have been reported in serum and peripheral blood mononuclear cells of Alzheimer's disease patients. Many of these observations in Alzheimer's disease patients are supported by findings in animal models, where there is also an increase in microglial activation that is accompanied by up-regulation of certain pro-inflammatory cytokines (including IL-1β) and chemokines that are co-localized with activated glia.

Neuroinflammation can act at multiple levels to affect neuronal function. It is associated with evidence of morphological changes including loss of processes, dystrophic processes and pyknotic nuclei. These changes are associated with a decrease in synaptic plasticity, specifically a reduction in long-term potentiation and a decrease in cognitive function. Happily, there is strong evidence that decreasing the inflammatory phenotype in the brain of aged animals decreases these cognitive impairments.

There is growing evidence that underlying inflammation can exert a negative effect on the progression of some neurodegenerative diseases. For example, systemic infections can exacerbate symptoms and trigger rapid progression in Parkinson's disease, multiple sclerosis and Alzheimer's disease, and infection influences recovery in stroke. This increased susceptibility to a stressor has been proposed to be a consequence of an underlying increase in the activation state of microglia. Recognizing that the limited success in clinical trials to date, in which anti-inflammatory agents are assessed in late chronic neurodegenerative disease, may be due to inappropriate timing of the intervention, Piazza and Lynch [1] have pointed out that an important challenge in this area is to identify the time at which anti-inflammatory intervention may be most effective.

Also at the meeting, giving one of two plenary lectures, Aviva Tolkovsky from the University of Cambridge spoke on cryptic cellular mechanisms of neurodegeneration. It is commonly accepted that neurons can die by apoptosis, and this mode of cell death is prevalent during embryonic development when many populations of neurons undergo apoptosis due to limited trophic support. Tolkovsky revealed how cryptic mechanisms of neurodegeneration operate in the responses of sympathetic neurons to CNTF (ciliary neurotrophic factor), the responses of sympathetic neurons to huntingtin exon 1 polyglutamine inclusions, and the responses of cortical neurons to the environmental toxin sodium arsenite [3]. Tolkovsky and colleagues have observed that neurons exposed to toxic insults activate a series of reactive changes that reflect a tension between survival and death signalling mechanisms. Activation of classical apoptosis pathways causes the neuron to react by initiating pro-survival signalling, which is counteracted by novel or ‘cryptic’ death mechanisms that overpower survival signalling and to which the neurons can react further by activating other survival pathways. Ultimately, this leads to death pathways that become very obscure. This is, of course, what is observed in neuronal cell death in degenerative conditions where elucidating the mechanism of cell death in neurodegenerative diseases is often confounded by the fact that neurons mount pro-survival responses to protect themselves from disease-related changes. Therefore neurons in the final stages of their demise often present a complex picture reflecting a struggle between pro-death factors and pro-survival responses, and teasing out the sequence of events can be a challenge.

Deniz Kirik from Lund University in Sweden addressed the question of whether animal models of Parkinson's disease are suitable for the development of neuroprotective therapies. The most commonly used animal models target the nigral dopaminergic neurons by use of specific neurotoxins such as 6-hydroxydopamine and MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). Although the 6-hydroxydopamine model is widely used and accepted for exploring the potential of cell-replacement strategies, since it reproduces very well the dopaminergic deficits by killing the midbrain dopaminergic neurons, it has several shortcomings as a model for neuroprotection, mainly because it does not fully recapitulate all of the events observed in the human disease. Specifically, neither the MPTP nor the 6-hydroxydopamine model reproduces the complex protein misfolding and aggregation that is observed in human disease. The recent genetic models that are being developed are proving promising. Kirik therefore advocates the use of a wider spectrum of pre-clinical in vivo animal models also encompassing genetic models as an essential element of translational Parkinson's disease therapeutics [4].

Jacqueline de Belleroche from Imperial College London spoke about neuroprotective strategies for ALS, another disease that affects motor function. Apart from the discovery of mutations in SOD-1 (superoxide dismutase-1), two novel causal genes have recently been identified, VAPB (vesicle-associated protein B) and TDP-43 (TAR DNA-binding protein 43). Current evidence indicates that mutant proteins have an increased propensity to aggregate, impairing normal neuronal function by affecting axoplasmic flow, nerve impulse conduction and communication between neurons. In fact, TDP-43 is a major component of ubiquitinated inclusions that are detected in ALS. This has highlighted the importance of molecular chaperones, particularly the HSPs (heat-shock proteins) that mediate many of these actions, facilitating the refolding of denatured proteins, preventing aggregation and transporting damaged proteins to the proteasome for degradation. De Belleroche and colleagues have shown that overexpression of the chaperone HSP27, shows beneficial effects in a mutant SOD-1 ALS model [5].

Therapeutic approaches in neurodegenerative diseases generally fall into three classes: neuroprotection, neuroregeneration and cell replacement therapies. On pp. xxx–xxx, Claire Kelly et al. [6] explore the problems associated with cell transplantation, focusing particularly on Huntington's disease, although the issues generally pertain to cell-replacement therapies for other neurodegenerative diseases. Huntington's disease is an autosomal-dominant inherited neurodegenerative disease that is characterized by loss of the MSNs (medium spiny neurons) of the striatum. As with other neurodegenerative diseases, cell-replacement strategies for Huntington's disease has met with limited success and still poses many challenges. Kelly et al. [6] give a comprehensive overview of the obstacles that are yet to be overcome before cell transplantation can become a reality for Huntington's disease patients. The major challenges all centre on the source and preparation of suitable tissue that can reproducibly be differentiated into the MSNs that are lost in Huntington's disease [7]. Initial clinical trials of cell transplantation have been undertaken using primary fetal striatal donor tissues. However, there are ethical and logistical issues surrounding the use of these tissues. There is limited availability of cells (multiple fetal donors are required for each transplantation), there is variability in a number of important factors including the donor age of the tissue, integrity of the tissue, the region dissected, the manner in which the cells are prepared for transplantation (i.e. cell suspension or small pieces) and freshness of the tissue. Kelly et al. [6] highlight the need for systematic study of the influence that these factors have on resulting graft survival, size, connectivity and, importantly, on functional recovery. Kelly et al. [6] highlight the need for alternative sources of cells for transplantation. The advantages and disadvantages surrounding the potential use of fetal neural precursor cells, embryonic stem cells and induced pluripotent stem cells are discussed in their paper [6]. They draw attention to the fact that, before each of these sources of cells can become a real possibility for therapeutic use, the same issues will need to be addressed, specifically issues relating to reproducibility, stability, safety and quality control, as well as those involving the directed differentiation into the correct neuronal phenotypes, and the functional integration of these into the complex neuronal circuits of the brain.

Psychopharmacology

In the first plenary talk at the Neuroscience Ireland conference, David Nutt (University of Bristol) discussed the psychopharmacology of anxiety, with reference to changes in brain structure measured using PET (positron-emission tomography) neuroimaging. Professor Nutt discussed the evidence indicating an involvement of GABA (γ-aminobutyric acid) and 5-hydroxytryptamine (serotonin) in the pathophysiology of anxiety disorders [8], and also the reasons behind the efficacy of selective 5-hydroxytryptamine-re-uptake inhibitors as drug treatments for anxiety.

John Waddington from the Royal College of Surgeons in Ireland discussed advances in understanding of genes which have been associated with susceptibility to schizophrenia. Using knockout mice with targeted deletion of genes implicated as risk factors for schizophrenia, such as NRG1 (neuregulin 1) and DISC1 (disrupted-in-schizophrenia 1), the impact of these genes on behaviour, and specifically on behaviour relevant to psychosis, is discussed on pp. xxx–xxx [9]. The normal function of DISC1 remains unclear, but it is widely expressed during development, and has effects on cell migration, neurite outgrowth and cell signalling. NRG1 is also widely acknowledged to be involved in neurodevelopment. Knockout mice deficient in the DISC1 gene show working memory impairment, reduced sociability, impairment in prepulse inhibition and latent inhibition, and increased locomotor activity in novel environments, all behavioural abnormalities with correlates to symptoms in humans with schizophrenia, and all of which can be reversed by antipsychotic treatment. Similar findings have been observed with NRG1-deficient mice. Discussion of the inherent difficulties with using genetically modified animals to study the effects of expression of a particular gene are discussed in their paper [9]. The fact that it is likely that compensatory and adaptive mechanisms may mask normal roles of genes in genetically modified animals is discussed. Furthermore, the likelihood that a single gene is responsible for schizophrenia is low and the issues of examining multiple gene interactions are also discussed, as well as the influence of the time-dependent expression, or changes in expression in genes.

In another invited talk at the conference, Chantal Martin-Soelch discussed depression, and the possibility that depression may be caused by a dysfunction of the cerebral reward system. On pp. xxx–xxx, Martin-Soelch [10] reviews evidence of reduced central dopaminergic transmission in depression and evidence of the involvement of dopamine in reward processing. Findings from functional MRI (magnetic resonance imaging) and PET reflecting dysfunction of the mesolimbic dopaminergic system in major depressive disorder are demonstrated [10]. Furthermore, Martin-Soelch discusses the need to specifically assess the neural correlates of anhedonia in depressed patients, and the necessity for further investigation of a possible blunted response to reward signals in major depressive disorder [10].

Pain

George Shorten (University College Cork) addressed the issue of chronic post-surgical pain, specifically with reference to breast surgery. On pp. xxx–xxx, factors such as altered electrical activity in damaged neurons following surgery, apoptosis of damaged neurons and microglial activation are discussed in the context of describing an alteration in the balance of excitatory and inhibitory systems involved in the transmission of the pain signals [11]. Sensation of pain results from activation of nociceptors by local inflammatory mediators. Pain persistence can be caused by subsequent intracellular signalling resulting in phosphorylation of ion channels, leading to increased neuronal excitability, which is manifest as primary hyperalgesia. Modification and modulation of the dorsal horn can result in secondary hyperalgesia because of an imbalance within the spinal cord between excitatory and inhibitory processes culminating in enhanced pain sensitivity outside an area of injury. The sensation of pain is subject to modulation by ascending and descending pathways. Opioids, endorphins, enkephalins, dynorphins, 5-hydroxytryptamine, noradrenaline, nitric oxide and glutamate are all known to influence the sensation of pain [11]. In addition, in their article, the potential role of GDNF (glial-derived neurotrophic factor), voltage-sensitive Ca2+ channels, voltage-sensitive Na+ channels and purinergic receptors is also addressed [11].

Steve McMahon from Kings College London discussed genetic determinants of pain sensitivity. Studies have shown that mutations in the TrkA (tropomyosin receptor kinase A) gene reduces the development of small-type nociceptor fibres, causing a deficiency in pain-sensory mechanisms and insensitivity to pain [12]. Nerve growth factor is well acknowledged to act as a mediator of inflammatory pain states in the periphery, through its interaction with TrkA receptors [12], resulting in marked changes in gene expression. The expression of voltage-sensitive ion channels such as Ca2+, K+ and, in particular, Na+ channels can be affected by nerve growth factor. Professor McMahon discussed how genetic factors have been highlighted in a recent twin study as genetic determinants to pain sensitivity. Mutations in Nav1.7 channels have been shown to be important in pain sensation [12].

Glial cell biology

Richard Reynolds from Imperial College London described how changes occur in oligodendrocyte–axon interactions in multiple sclerosis. Neurofascin-155 has been used as an oligodendrocyte-specific marker which highlights nodal architecture. Disruption of the nodal architecture is observed in regions of axons with axon demyelination, and in axons showing signs of stress, but without apparent active demyelination [13].

Stephen McQuaid (Queen's University Belfast) discussed the effects of disruption of blood–brain barrier function on glial cell activity in multiple sclerosis. It is well recognized that blood–brain barrier impairment extends far beyond areas of contrast-enhancing lesions, which are known to be associated with inflammation and demyelination. Indeed, it has been suggested that blood–brain barrier impairment may precede the development of demyelinating lesions and acute inflammation. On pp. xxx–xxx, studies using confocal microscopy to investigate tight junction proteins and leaked fibrinogen in human autopsy samples are discussed [14]. Findings show endothelial anomalies that are particularly associated with active lesions in white matter in multiple sclerosis. Tight junctions in endothelial cells maintain the integrity of the blood–brain barrier, restricting access of molecules to the central nervous system. Leaked fibrinogen from plasma has recently been shown to activate microglia and may underpin the inflammation associated with multiple sclerosis. Evidence suggesting that altered expression of tight junction proteins may affect glial cell function and that disruption of the blood–brain barrier in multiple sclerosis may be strongly associated with demyelination is discussed [14].

Conclusion

The second Neuroscience Ireland Conference at National University of Ireland, Galway, was a very successful meeting with a wide range of topics, as can be seen from the following articles in this issue of Biochemical Society Transactions. Many current issues and challenges in these diverse areas of neuroscience were highlighted, underscoring the need for continued research.

2nd Neuroscience Ireland Conference: Independent Meeting held at National University of Ireland, Galway, Co. Galway, Ireland, 28–29 August 2009. Organized and Edited by Karen Doyle (National University of Ireland, Galway, Ireland).

Abbreviations

     
  • ALS

    amyotrophic lateral sclerosis

  •  
  • DISC1

    disrupted-in-schizophrenia 1

  •  
  • HSP

    heat-shock protein

  •  
  • IL

    interleukin

  •  
  • MPTP

    1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

  •  
  • MSN

    medium spiny neuron

  •  
  • NRG1

    neuregulin 1

  •  
  • PET

    positron-emission tomography

  •  
  • SOD-1

    superoxide dismutase 1

  •  
  • TDP-43

    TAR DNA-binding protein 43

The meeting was supported by The Biochemical Society, The Anatomical Society of Great Britain and Ireland, and Science Foundation Ireland.

References

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