Experiments examine modulation of thalamic neuronal and network activities by the inhibitory neurotransmitter g-aminobutyric acid (GABA), and by neuropeptide Y (NPY) and vasoactive intestinal polypeptide (VIP). One series of experiments focuses on molecular differences in GABA type A receptors in neurons of mouse nucleus reticularis (nRt) and the ventrobasal relay nucleus (VB), and the functional and pharmacological consequences of receptor subunit heterogeneity in these structures, whose reciprocal connectivity underlies thalamic rhythm generation. The hypothesis that alpha3 subunit-containing receptors in nRt cells confer sensitivity to the benzodiazepine anticonvulsant clonazepam will be tested in mutated mice. The role of beta3-containing receptors in generating prolonged inhibitory postsynaptic currents (IPSCs) that have an anti-rhythmogenic action in nRt will be examined. A second group of experiments explores actions of NPY and VIP on neuronal and circuit activities in mice and rats. The hypothesis that NPY is released during intense intrathalamic oscillatory activity, and in turn has anti-oscillatory effects, will be tested. The possibility that chronic dosing of the anticonvulsant valproic acid in vivo enhances expression of NPY in nRt cells, resulting in increased release, will be explored. VIP effects on membrane properties and synaptic currents in nRt and VB neurons, and on thalamic circuit oscillations will be studied. Techniques will include whole cell patch clamp recordings of IPSCs and voltage-dependent membrane currents; application of pharmacological agents; single cell RT-PCR from neurons of in vitro thalamic slices; in situ hybridization; the use of mice mutated for various alpha and beta GABAA receptor subunits; and measurements of peptides released from thalamic slices. The long-term goals are to understand the control of thalamic neuronal and circuit activities and potential abnormalities that may underlie pathophysiological states such as absence epilepsy. ? ? ?
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