Effects of the β-amino acid antagonist TAG on thalamocortical inhibition

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Abstract

Chemical transmission at inhibitory synapses in thalamus may involve receptor activation by β-amino acids and glycine, as well as GABA. Given their hypothesized roles, we investigated effects of the putative β-amino acid antagonist 6-aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine-1,1-dioxide (TAG) on synaptic inhibition in dorsal thalamus. We performed whole-cell recordings in 200–250 μm sections and immunocytochemical (ICC) studies in ventrobasal thalamus of rat brain (P12-P14). Stimulation of medial lemniscus evoked inhibitory postsynaptic currents (IPSCs) which were purely glycinergic or GABAAergic, or most commonly mixed glycinergic and GABAAergic responses, based on abolition by strychnine, bicuculline, or combined antagonism. TAG antagonized mixed IPSCs (IC50 ∼70 μM) in a manner distinguishable from classical glycine and GABAA receptor antagonists. TAG (250 μM) reduced the amplitude of glycinergic components which had a decay time constant of ∼9 ms or ∼230 ms by 45–50%, and a GABAAergic component which had a decay time constant of ∼40 ms by ∼60%. As in the glycinergic component, TAG reduced the amplitude of infrequently occurring, pure glycinergic IPSCs. Surprisingly, TAG had no effect on pure GABAAergic IPSCs, with a decay time constant of ∼20 ms that correlated to kinetics of GABA-activated channels. ICC studies showed co-localization of α1/2 glycine and α4 GABAA receptors at inhibitory synapses. Activation of α4 receptors by β-amino acids may contribute to the GABAAergic component of mixed IPSCs. The short and long-duration glycinergic IPSCs had decay time constants that correlated to the burst durations of single channels opened by β-amino acids and glycine. Overall, the effects of TAG implicate β-amino acid involvement in GABAAergic and glycinergic transmission.

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