Effects of the beta-amino acid antagonist TAG on thalamocortical inhibition.
Chemical transmission at inhibitory synapses in thalamus may involve receptor activation by beta-amino acids and glycine, as well as GABA. Given their hypothesized roles, we investigated effects of the putative beta-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 microm 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 GABA(A)ergic, or most commonly mixed glycinergic and GABA(A)ergic responses, based on abolition by strychnine, bicuculline, or combined antagonism. TAG antagonized mixed IPSCs (IC(50) approximately 70 microM) in a manner distinguishable from classical glycine and GABA(A) receptor antagonists. TAG (250 microM) reduced the amplitude of glycinergic components which had a decay time constant of approximately 9 ms or approximately 230 ms by 45-50%, and a GABA(A)ergic component which had a decay time constant of approximately 40 ms by approximately 60%. As in the glycinergic component, TAG reduced the amplitude of infrequently occurring, pure glycinergic IPSCs. Surprisingly, TAG had no effect on pure GABA(A)ergic IPSCs, with a decay time constant of approximately 20 ms that correlated to kinetics of GABA-activated channels. ICC studies showed co-localization of alpha(1/2) glycine and alpha(4) GABA(A) receptors at inhibitory synapses. Activation of alpha(4) receptors by beta-amino acids may contribute to the GABA(A)ergic 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 beta-amino acids and glycine. Overall, the effects of TAG implicate beta-amino acid involvement in GABA(A)ergic and glycinergic transmission.
Mathers
David A
DA
Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, British Columbia, Canada. mathers@interchange.ubc.ca
McCarthy
Sarah M
SM
Cooke
James E
JE
Ghavanini
Ahmad A
AA
Puil
Ernest
E