Activation of metabotropic glutamate receptors (mGluR) by corticothalamic afferents can lead to long-term depression of gap junction coupling between neurons of the thalamic reticular nucleus (TRN). The research proposed will identify the specific mGluR subtype that mediates this effect, determine the duration of the reduced coupling, and identify the intracellular signaling molecules that transduce the signal between the identified mGluR and the gap junctions. Thalamocortical afferents to the TRN will be studied for their effect on gap junction coupling. In addition, both glutamatergic afferents to the TRN, corticothalamic and thalamocortical, will be stimulated simultaneously and asynchronously to understand how their interaction affects gap junction coupling in the TRN. The specific questions addressed in this proposal include the following: 1) Which metabotropic glutamate receptor subtype mediates long-term depression of TRN gap junctions? 2) How long does the depressed coupling last? 3) Which molecules are necessary for signaling between mGluRs and gap junctions? 4) Do thalamic inputs independently affect coupling? Do thalamic and cortical inputs interact to affect coupling in a complex manner? The TRN is a key component of the thalamocortical circuitry and is involved in sleep induction and some forms of seizures. Understanding how the two glutamatergic inputs to the TRN modulate electrical communication within the TRN may lead to treatments for some seizure and sleep disorders and a more accurate understanding of the thalamocortical circuitry. All experiments will involve dual whole-cell current clamp recordings of pairs of TRN neurons in a rat or mouse brain slice preparation. Afferent stimulation is produced with a small bipolar electrode placed in the appropriate fiber tract in the brain slice. Specific mGluR agonists and antagonists will be added to the bath, sometimes in conjunction with glutamatergic afferent stimulation, to identify the specific mGluR mediating the reduced coupling effect. Selective activators and inhibitors of intracellular signal transduction molecules will be used to identify the molecules necessary for transducing the signal between the mGluRs and the gap junctions. ? ? ?
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