Reorganization of GABAergic circuits maintains GABA_A receptor‐mediated transmission onto CA1 interneurons in α1‐subunit‐null mice

Abstract

The majority of hippocampal interneurons strongly express GABA(A) receptors containing the alpha1 subunit, suggesting that inhibitory control of interneurons is important for proper function of hippocampal circuits. Here, we investigated with immunohistochemical and electrophysiological techniques how these GABA(A) receptors are replaced in mice carrying a targeted deletion of the alpha1-subunit gene (alpha1(0/0) mice). Using markers of five major populations of CA1 interneurons (parvalbumin, calretinin, calbindin, neuropeptide Y and somatostatin), we show that these interneurons remain unaffected in alpha1(0/0) mice. In triple immunofluorescence staining experiments combining these markers with the GABA(A) receptor alpha1, alpha2 or alpha3 subunit and gephyrin, we demonstrate a strong increase in alpha3- and alpha2-GABA(A) receptors clustered at postsynaptic sites along with gephyrin in most CA1 interneurons in alpha1(0/0) mice. The changes were cell type-specific and resulted in an increased number of GABAergic synapses on interneurons. These adjustments were mirrored functionally by retention of spontaneous IPSCs with prolonged decay kinetics, as shown by whole-cell patch-clamp recordings of CA1 interneurons. However, a significant decrease in frequency and amplitude of miniature IPSCs was evident, suggesting reduced affinity of postsynaptic receptors and/or impaired vesicular GABA release. Finally, to assess whether these compensatory changes are sufficient to protect against a pathological challenge, we tested the susceptibility of alpha1(0/0) mice against kainic acid-induced excitotoxicity. No genotype difference was observed in the effects of kainic acid, indicating that the absence of a major GABA(A) receptor subtype is functionally compensated for in hippocampal interneurons by a reorganization of inhibitory circuits.

Cortical Glutamatergic Neurons Mediate the Motor Sedative Action of Diazepam

“…Global deletion of the ␣1 subunit gene results in a marked compensatory overexpression of the GABA A receptor ␣2, ␣3, and ␣4 subunits, selectively in those brain regions where the ␣1 subunit is absent (Kralic et al, 2002aSchneider Gasser et al, 2007). Up-regulation probably takes place at the level of translation, without increase in subunit gene transcription, as shown by several studies (Bosman et al, 2005b).…”

Molecular and functional heterogeneity of GABAergic synapses

“…The multiplicity of GABA A R underlies molecular and functional heterogeneity of GABAergic synapses, as well as differential targeting to extrasynaptic versus postsynaptic sites. There is evidence that receptors differing in α subunit variant are functionally not interchangeable, and that only GABA A R targeted postsynaptically contribute to formation of gephyrin clusters [56,57]. Therefore, interactions of GABA A R subtypes with gephyrin and other GABAergic PSD proteins are likely more heterogeneous and synapse-specific than GlyR-gephyrin interactions.…”

Expression of GABAA receptor α1 subunit mRNA and protein in rat neocortex following photothrombotic infarction

“…Importantly, GABAergic inhibition appeared to be functional in GABA A R α 1 knockout mice in that the acute and chronic excitotoxic and epileptogenic action of kainic acid was not altered compared with wild-type mice (Schneider Gasser et al, 2007).…”

“…Targeted depletion of the GABA A R α 1 subunit gene in knockout mice resulted in a viable phenotype with more than 50% of total GABA A R loss (Sur et al, 2001;Kralic et al, 2002); absence of the α 1 subunit was compensated by up-regulation of other GABA A R subtypes, clustering, and reorganization of GABAergic circuits (Kralic et al, 2006, Schneider Gasser et al, 2007. Importantly, GABAergic inhibition appeared to be functional in GABA A R α 1 knockout mice in that the acute and chronic excitotoxic and epileptogenic action of kainic acid was not altered compared with wild-type mice (Schneider Gasser et al, 2007).…”