Book of abstracts - British Neuroscience Association

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48.03 Alcohol dependence; what happens when drinking stops Little H Alcohol dependence continues for months or even years after an alcoholic manages to stop drinking, and the great majority of alcoholics return to excess alcohol drinking. For the last few years, my research group has been investigating changes in neuronal function and behaviour that occur during the abstinence phase after withdrawal from chronic alcohol consumption. We found that long term alcohol intake and withdrawal caused a long lasting sensitisation to the effects of other drugs of dependence, amphetamine, cocaine and nicotine. We have also demonstrated changes in mesolimbic dopamine transmission that last long after the end of the acute alcohol withdrawal phase in rodents. Such neuronal changes may be involved in the prolonged effects of chronic alcohol consumption that make the dependence so difficult to treat. Changes were also found in the concentrations of glucocorticoid in specific brain areas, particularly the prefrontal cortex and hippocampus, even though the plasma concentrations returned to control levels. In other brain areas, such as the cerebellum, the corticosterone concentrations were not different from controls. These alterations were seen for several weeks after withdrawal from the chronic alcohol treatment. These glucocorticoid changes may also be involved in the development of dependence or other prolonged effects of alcohol. 49.01 Ubiquitin dependent downregulation of GABAA receptors Arancibia-Carcamo I L (1), Michels G (2), Armstrong-Gold C(2), Lumb M J (1), Moss S J (2), Kittler J T (3) 1. Pharmacology 3. Physiology, University College London. London. UK, 2. Neuroscience. University of Pennsylvania. PA. USA γ-amino-butyric acid type A (GABAA) receptors are the major sites of fast synaptic transmission in the central nervous system and can be assembled from 7 subunit classes: α1-6, β1-3, γ1-3, δ, ε, π, and θ. Although expression of receptor α and β subunits can produce functional GABAgated chloride channels the presence of the γ2 subunit within the GABAA receptor complex has been shown to play a key role in clustering and synaptic targeting. Here we investigate the molecular mechanisms for the regulation of the endocytic sorting of GABAA receptors and their role in synaptic inhibition. In the present study we show a role for the GABAA receptor γ2 subunit in regulating the lysosomal targeting of internalized GABAA receptors. Microscopy and biochemical experiments revealed that the γ2 subunit of GABAA receptors confers an enhancement in the targeting of GABAA receptors to a degradative pathway after internalization from the plasma membrane. Using a chimeric system and site directed mutagenesis together with antibody feeding and quantitative confocal microscopy we have identified a specific lysosomal targeting amino acid sequence within the γ2 subunit that can be regulated by ubiquitination. Importantly, using a combination of electrophysiological, biochemical and immunofluorescence techniques we were able to show how regulating the endocytic sorting fate of GABAA receptors plays an important role in modulating inhibitory synaptic strength. 49.02 SUMOylation regulates kainate receptor endocytosis and synaptic transmission Martin S, Nishimune A, Mellor J, Henley J M MRC Centre for Synaptic Plasticity, Anatomy Department, University Walk, University of Bristol, Bristol, BS8 1TD, UK., Small Ubiquitin-like MOdifier protein (SUMO) regulates transcriptional activity and the translocation of proteins across the nuclear membrane but little is known about the wider cellular role of protein SUMOylation. We have found a completely new role for protein SUMOylation in the regulation of KAR endocytosis that, in turn, modulates synaptic transmission. GluR6 SUMOylation is necessary for agonist-dependent internalisation but not for internalisation per se. We anticipate that, like phosphorylation and ubiquitination, protein SUMOylation may have complex, varied and crucial roles in determining the fate of modified synaptic proteins and will have far reaching implications for the understanding of synaptic function. 49.03 Pruning and loss of excitatory synapses by a postsynaptic ubiquitin ligase Ehlers M Department of Neurobiology, Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina, USA E3 ubiquitin ligases mediates the transfer of ubiquitin onto diverse substrate proteins, thereby tagging proteins for proteosomal degradation. Here we identify a RING domain E3 ligase (REL) that resides near the postsynaptic membrane of glutamatergic synapses and regulates synaptic function. In hippocampal neurons, postsynaptic expression of REL dampens excitatory synaptic transmission and causes a marked loss of excitatory synapses. Conversely, expression of mutant forms of REL or reduced expression of endogenous postsynaptic REL, profoundly enhances synaptic efficacy, triggers a proliferation of glutamatergic synapses, and increases vulnerability to synaptic excitotoxicity. By regulating the number and strength of excitatory synapses, REL controls the normal elaboration of synaptic circuitry. Further, increased excitatory drive produced by disruption of REL function may contribute to neuronal pathophysiology Page 72/101 - 10/05/2013 - 11:11:03
49.04 Regulation of synaptic function by ubiquitin-specific protease 14 Wilson S Dept of Neurology, University of Alabama, Birmingham, Alabama USA The ataxia mutation (axJ) is a recessive neurological mutation that results in reduced growth, ataxia and hind-limb muscle wasting in mice. The axJ gene encodes ubiquitin-specific protease 14 (Usp14), a deubiquitinating enzyme (DUB) that associates with the proteasome. Transgenic rescue of the axJ mice with neuronal-specific expression of Usp14 demonstrated that the full-length form of Usp14 was sufficient to restore viability and motor system function to the axJ mice. Biochemical analysis showed that the ubiquitin-hydrolyase activity of this form of Usp14 is dependent upon the presence of proteasomes, and neuronal expression of full-length Usp14 was able to restore the levels of monomeric ubiquitin in the brains of axJ mice. However, axJ-rescued mice still displayed the Purkinje cell axonal swellings that are seen in the axJ mice, indicating that this cerebellar alteration is not the primary cause of the axJ movement disorders. Examination of spinal cords from the axJ mice did reveal the presence of pathological markers of motor neuron dysfunction. While the axJ mice do not lose motor neurons, analysis of neuromuscular junction demonstrated that the axJ mice have defects in vesicle recycling and display increased synaptic rundown. These results show that the motor defects observed in the axJ mice are due to a neuropathic disease rather than a muscular disorder, and suggest that changes in proteasomal function may contribute to neuromuscular junction disease observed in the axJ mice. 50.01 Synaesthesia: a window into genetic and behavioural bases of multisensory processing Newell F School of Psychology and Institute of Neuroscience, Trinity College Dublin Synaesthesia is a rare condition where particular stimuli elicit additional sensory experiences. Although there are many different subtypes of synaesthesia we attempted to elucidate the processes common to these various forms. First, we investigated the heritability of synaesthesia by conducting a large-scale study of the nature of synaesthetic experiences within familial settings. We recruited 53 synaesthetes and 42% of these probands reported a first-degree relative with synaesthesia. Interestingly, we found that different types of synaesthesia can occur within the same family, suggesting that various types of synaesthesia are fundamentally related at the genetic level. In a second series of studies we assessed the multisensory nature of synaesthetic experiences. We found that colours induced to letter stimuli are independent of the encoding modality in that the visual, auditory and tactile versions of a letter all induced the same colour. This finding suggested both that grapheme-colour synesthesia may be mediated through vision and that synaesthesia is linked more to perceptual decisions than sensory input. Consistent with these suggestions, we found evidence that i) synaesthetes report more vivid mental images than controls and, as revealed through the “McGurk effect” ii), that synaesthetic experiences are driven by higher-level perceptual output. Our data indicate that various forms of synaesthesia have a common etiology and share basic processes of multisensory perception. 50.02 A Multisensory spin on self-motion perception Smith S School of Psychology, University College Dublin Moving through one’s environment is a naturally multisensory task involving a coordinated set of sensorimotor processes that encode and compare information from visual, vestibular, proprioceptive, motor-corollary, and cognitive inputs. Interaction between visual and vestibular information in the perception of self-motion has been reported in the literature for over 50 years [e.g. Battersby et at, 1956]. The importance of visual inputs for estimation of self-motion direction (heading) was first recognised by Gibson (1950) who postulated that heading could be recovered by locating the focus of expansion (FOE) of the radially expanding optic flow field coincident with forward translation. We have recently shown [Stone, Smith and Bush, 2004] that humans with intact vestibular function can estimate their direction of linear translation using vestibular cues alone with as much certainty as they do using visual cues. Here we report the results of an ongoing investigation of self-motion estimation that addresses whether visual and vestibular information can be combined in a statistically optimal fashion. We discuss our results from the perspective that successful execution of self-motion behaviour requires the computation of one’s own spatial orientation relative to the environment. A combined intracranial EEG, MEG and fMRI look at audiovisual speech integration. 50.03 The Case for Feedforward Multisensory Convergence during Early Cortical Processing Foxe J Institute of Neuroscience, Trinity College Dublin; The Cognitive Neurophysiology Laboratory, Nathan S. Kline Institute for Psychiatric Research. 140 Old Orangeburg Road, Orangeburg, New York, USA; The prevailing hierarchical model of sensory processing in the brain holds that different modalities of sensory information emanating from a single object are analyzed extensively during passage through their respective unisensory processing streams before they are combined in higher-order “multisensory” regions of cortex. Because of this view, multisensory interactions that have been found at early, putatively “unisensory” cortical processing stages during hemodynamic imaging studies have been assumed to reflect feedback modulations that occur subsequent to multisensory processing in the higher-order multisensory areas. In this talk, I will consider findings that challenge an exclusively feedback interpretation of early multisensory integration effects. First, high-density electrical mapping studies in humans have shown that multisensory convergence and integration effects can occur so early in the timecourse of sensory processing, that purely feedback mediation becomes extremely unlikely. Second, direct neural recordings in monkeys show that in some cases, convergent inputs at early cortical stages have physiological profiles characteristic of feedforward, rather than feedback inputs. Third, damage to higher order integrative regions in humans often spares the ability to integrate across sensory modalities. Finally, recent anatomic tracer studies have reported direct anatomical connections between primary visual and auditory cortex. These findings make it clear that multisensory convergence at early stages of cortical processing results from feedforward, as well as feedback and lateral connections, thus using the full range of anatomical connections available in brain circuitry. Page 73/101 - 10/05/2013 - 11:11:03
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Page 31 and 32: 18.03 Finding cells for replacement
Page 33 and 34: 20.01 Cannabinoid neuropharmacology
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Book of abstracts - British Neuroscience Association

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