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Conférence mensuelle - Trevor SmartPlasticity of inhibitory synaptic neurotransmission

Abstract :

Conférence mensuelle  de l'Axe Synapse

 The presentation will explore the properties of GABA-mediated synaptic inhibition
- in particular how receptor plasticity mechanisms can affect cell excitability in an input and a GABA receptor subunit specific manner. It will also include how endogenous neuromodulators can affect behaviour by selectively affecting GABA inhibition via specific GABA-A receptor isoforms.  





Selected publications

Stoichiometry of δ subunit containing GABA(A) receptors.
Journal article ; 2014 ; Br J Pharmacol ; England
links: IRIS ; UCL Discovery ; doi ; author's
authors : Patel B et al.

Protein kinase C regulates tonic GABA(A) receptor-mediated inhibition in the hippocampus and thalamus
links: IRIS ; UCL Discovery ; doi ; author's
authors : Bright DP,Smart TG

Methods for recording and measuring tonic GABAA receptor-mediated inhibition.
Journal article ; 2013 ; Front Neural Circuits ; Switzerland
links: IRIS ; UCL Discovery ; doi ; author's
authors : Bright DP,Smart TG

Mutations in the Gabrb1 gene promote alcohol consumption through increased tonic inhibition.
Journal article ; 2013 ; Nat Commun ; England
links: IRIS ; UCL Discovery ; doi ; author's
authors : Anstee QM et al.

Disrupting the clustering of GABA(A) receptor alpha 2 subunits in the frontal cortex leads to reduced gamma-power and cognitive deficits
links: IRIS ; UCL Discovery ; doi ; author's
authors : Hines RM et al.

Protein kinase C regulates tonic GABA(A) receptor-mediated inhibition in the hippocampus and thalamus.
Journal article ; 2013 ; Eur J Neurosci ; France
links: IRIS ; UCL Discovery ; doi ; author's
authors : Bright DP,Smart TG

Tyrosine phosphorylation of GABAA receptor γ2-subunit regulates tonic and phasic inhibition in the thalamus.
Journal article ; 2013 ; J Neurosci ; United States
links: IRIS ; UCL Discovery ; doi ; author's
authors : Nani F et al.

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Scientific focus :

Controlling the innate excitability of neurons is vital for a healthy nervous system. There are various ways of achieving this aim, but by far the most important involves the inhibitory transmitter, GABA. Fast synaptic inhibition is achieved by rapid activation of GABA-A receptors whilst longer term modulatory effects on excitability are accomplished by GABA-B receptor activation. It is increasingly clear that there are many different isoforms of GABA-A receptors and these appear, in particular examples, to be targeted to discrete areas of the brain, and within single neurones, to discrete inhibitory synapses. Given the critical role(s) these receptors play in neuronal function, they form a logical target for therapeutic agents to ameliorate uncontrolled neuronal excitability, in addition to being involved in numerous neurological disorders, such as epilepsy and anxiety. Our research in neuroscience at UCL is supported by long-term programme grant funding from the Medical Research Council and the Wellcome Trust. We use multidisciplinary integrated approaches, based on electrophysiology, cell and molecular biology, imaging and neurogenetics, to elucidate the molecular and network properties of GABA receptors. These techniques, for network, whole-cell synaptic and single channel studies, are used in native neurones coupled with optical and genetic adaptations to modify the response profile of GABA-A receptors. To gain proof-of-principle for our manipulations of GABA-A receptor structure-function, we employ numerous DNA or RNA tranfection methods (allowing receptor expression in cells following viral infection, direct microinjection and lipofection). In addition, we are also using imaging/optical techniques, with various fluorophores and photoactivated caged compounds, to enable the tracking in live cells of receptor subunits in real time into and out of inhibitory synapses. At the synaptic and network levels, similar approaches are used to study the physiological control of inhibitory transmission and synaptic plasticity by retrograde and autocrine messengers. This also includes how other endogenous regulators in the nervous system (e.g., phosphorylation and neurosteroids) can modulate the function of specific GABA-A receptors at specific inhibitory synapses to affect network behaviour. Overall, our major objective is to provide a complete molecular description of the therapeutically important GABA receptor classes that will enable a deeper understanding of their role in neuronal networks in both healthy and diseased states.