Award details

Inhibitory neurotransmission in the thalamus and modulation by general anaesthetics and sedatives.

Reference	BB/C509923/1
Principal Investigator / Supervisor	Professor Jeremy Lambert
Co-Investigators / Co-Supervisors	Dr Delia Belelli
Institution	University of Dundee
Department	Neuroscience
Funding type	Research
Value (£)	219,460
Status	Completed
Type	Research Grant
Start date	01/01/2005
End date	31/08/2008
Duration	44 months

Abstract

In a collaboration (BBSRC CASE award) that used transgenic mice harbouring specific mutations of GABAA receptor subunits, we and others have demonstrated the sedative and anaesthetic effects of the general anaesthetic etomidate to be mediated by distinct GABAA receptor subtypes that incorporate the beta2 and beta3 subunit respectively. Determining how general anaesthetics act should permit a better understanding of how changes to neuronal signalling influence behaviour. The thalamus is a brain area implicated in some of the behavioural actions of general anaesthetics. Furthermore, neurones of the ventero basilis (VB) complex and nucleus reticularis (nRT) exhibit a differential distribution of the beta 2 and beta 3 subunit respectively. Here we aim to: 1) Utilise the whole-cell patch clamp technique to compare wild type (WT) and transgenic mice (harbouring specific subunit mutations that impart insensitivity to etomidate or benzodiazepines) as a finger print to better define the synaptic GABAA receptors that mediate inhibitory transmission in neurones of the nucleus reticularis (nRT) and ventero basilis (VB) complex and the extrasynaptic GABAA receptors of the VB. The extrasynaptic receptors of the VB are of particular interest as our preliminary data demonstrate these receptors to mediate a large tonic conductance, be physiologically and pharmacologically distinct and exceptionally sensitive to some anaesthetics. 2) Investigate the relative effects of a range of iv general anaesthetics and sedatives (that differ in their selectivity for GABAA receptor subtypes) on GABAA receptors of nRT and VB neurones. The study will be extended to compare the effects of these sedative/anaesthetics on synaptic GABAA receptors of cortical pyramidal cells as these neurones receive excitatory output from the thalamus and are reported to differ from the thalamus in their anaesthetic sensitivity. 3) Use single cell current clamp and extracellular recordings to record oscillatory synaptic activity in the thalamus and the effects of general anaesthetics. With an in vitro thalamic slice preparation sustained oscillations (that are dependent upon nRT and VB GABAA receptors) may be elicited by electrical stimulation. Such activity probably underpins the waves, or spindles associated with drowsiness and sleep. However, the relative role in this activity of extrasynaptic and synaptic GABAA receptors is little understood. By using a combination of GABAA receptor subtype selective anaesthetics/sedatives and mutant mice we will elucidate the contribution of these receptors to this activity and their importance as targets for anaesthetic action. This study will allow a much better understanding of the role of inhibitory transmission, and in particular GABAA receptor subtypes in the functioning of the thalamus and their role in mediating the effects of anaesthetics.

Summary

unavailable

Committee	Closed Committee - Animal Sciences (AS)
Research Topics	Neuroscience and Behaviour
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

I accept the terms and conditions of use (opens in new window)

export PDF file

back to list new search