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

Jun 8, 2007The European journal of neuroscience

Changes in inhibitory brain circuits preserve receptor signals to memory-area interneurons in mice lacking a key receptor part

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Abstract

In alpha1(0/0) mice, GABA(A) receptors containing the alpha2 and alpha3 subunits increased significantly in hippocampal interneurons.

Major populations of CA1 interneurons remain unaffected despite the deletion of the alpha1 subunit gene.
Increased clustering of alpha2- and alpha3-GABA(A) receptors at postsynaptic sites along with gephyrin was observed.
The number of GABAergic synapses on interneurons increased following the deletion of the alpha1 subunit.
Whole-cell patch-clamp recordings indicated retention of spontaneous inhibitory postsynaptic currents (IPSCs) with prolonged decay kinetics.
A decrease in frequency and amplitude of miniature IPSCs suggests potential reduced receptor affinity or impaired neurotransmitter release.
No genotype difference in susceptibility to kainic acid-induced excitotoxicity indicates functional compensation in inhibitory circuits.

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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.

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

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