Prolongation of Hippocampal Miniature Inhibitory Postsynaptic Currents in Mice Lacking the GABA_AReceptor α1 Subunit

Abstract

. Prolongation of hippocampal miniature inhibitory postsynaptic currents in mice lacking the GABA A receptor ␣1 subunit. J Neurophysiol 88: 3208 -3217, 2002. 10.1152/jn.00885.2001. GABA A receptors (GABA A -Rs) are pentameric structures consisting of two ␣, two ␤, and one ␥ subunit. The ␣ subunit influences agonist efficacy, benzodiazepine pharmacology, and kinetics of activation/deactivation. To investigate the contribution of the ␣1 subunit to native GABA A -Rs, we analyzed miniature inhibitory postsynaptic currents (mIPSCs) in CA1 hippocampal pyramidal cells and interneurons from wild-type (WT) and ␣1 subunit knock-out (␣1 KO) mice. mIPSCs recorded from interneurons and pyramidal cells obtained from ␣1 KO mice were detected less frequently, were smaller in amplitude, and decayed more slowly than mIPSCs recorded in neurons from WT mice. The effect of zolpidem was examined in view of its reported selectivity for receptors containing the ␣1 subunit. In interneurons and pyramidal cells from WT mice, zolpidem significantly increased mIPSC frequency, prolonged mIPSC decay, and increased mIPSC amplitude; those effects were diminished or absent in neurons from ␣1 KO mice. Nonstationary fluctuation analysis of mIPSCs indicated that the zolpidem-induced increase in mIPSC amplitude was associated with an increase in the number of open receptors rather than a change in the unitary conductance of individual channels. These data indicate that the ␣1 subunit is present at synapses on WT interneurons and pyramidal cells, although differences in mIPSC decay times and zolpidem sensitivity suggest that the degree to which the ␣1 subunit is functionally expressed at synapses on CA1 interneurons may be greater than that at synapses on CA1 pyramidal cells.

Synapse formation and clustering of neuroligin-2 in the absence of GABA A receptors

“…The mean amplitude of miniature events (mIPSCs) recorded in the presence of 1 M tetrodotoxin (TTX) was significantly smaller in GABA A ␣1 KO mice compared with WT littermates, whereas their decay time-constant was prolonged in PCs of mutants (Table S2). These findings are consistent with several other studies showing that loss of GABA A ␣1 results in a marked reduction of IPSC frequency and amplitude, and in a prolongation of postsynaptic responses (27)(28)(29)(30).…”

ErbB4 reduces synaptic GABA A currents independent of its receptor tyrosine kinase activity

“…4 C and D) in ErbB4+ interneurons, consistent with a reduction of rapidly decaying synaptic currents. Because GABAR α1 confers rapid decay kinetics (12,34,35), our results indicate that NRG2-ErbB4 association preferentially targets synaptic α1 subunit-containing GABARs.…”

“…Our data show that NRG2 causes a robust somatodendritic-wide decrease of GABAR α1 surface labeling and colocalization with gephyrin-positive puncta, consistent with the reduction of mIPSC amplitude. In addition, the residual synaptic α1-and α2-containing GABARs may contribute to the prolonged decay kinetics (12,34). As NRG2 effects require PKC activity and clathrin-dependent endocytosis (Fig.…”

“…In the hippocampus, the GABA A receptor α1 subunit (GABAR α1), which imparts rapid decay kinetics (12), is also selectively expressed in subsets of inhibitory interneurons, especially in PV+ neurons (13,14). Furthermore, a mutation in GABRA1 has been linked to absence seizures (15), and heterozygous Gabra1-null mice show cortical absence epileptiform activity (16).…”

Effects of status epilepticus on hippocampal GABAA receptors are age-dependent

“…GABARs containing an α1 subunit are more highly augmented by type I benzodiazepine agonists such as zolpidem than GABARs containing any other α-subtype (Pritchett et al, 1989;Barnard et al, 1998), although GABARs containing other α-subunits can respond to zolpidem at high concentrations (Goldstein et al, 2003). There was significantly more augmentation of GABAinduced currents by 100 nM zolpidem in DGNs from P10-SE rats (94.6±11.4%) compared with DGNs from either lithium-control rats (41.8±4.2%) or naive-control rats (63.9±5.3%; Fig.…”