CHARACTERIZATION OF GABA<SUB >A</SUB> RECEPTOR SUBUNITS AT PREFRONTAL AXO-AXONIC SYNAPSES IN SCHIZOPHRENIA

Accumulating evidence highlights prefrontal GABAergic dysfunction as a hallmark of the underlying pathology in schizophrenia, with notable abnormalities in the gene expression of GABA_A receptors (GABA_ARs). Among the implicated cell types, chandelier cells are of particular interest due to their unique GABAergic inhibitory control over pyramidal cell output via specialized axo-axonic synapses at the axon initial segment. Molecular alterations of these synapses may contribute to the aberrant network activity and cognitive deficits, characteristic of the disorder.
Here, we studied the GABA_AR subunit composition of axo-axonic synapses in the dorsolateral prefrontal cortex of control and schizophrenic subjects. We employed a highly sensitive, quantitative, multiplexed postembedding immunofluorescent labeling method to localize various GABA_AR subunits and synaptic markers at individual synapses in thin, resin-embedded sections of postmortem fixed human tissue.
Axo-axonic synapses were identified by presynaptic vesicular GABA transporter (VGAT) and postsynaptic neuroligin-2 (NL2) labeling associated with TRIM46 labeled axon initial segments in all cortical layers. Multiple rounds of immunofluorescent labeling for six GABA_AR subunits (α1, α3, β1, β2, β3 and γ2) were performed at these axo-axonic synapses. Synapse size, VGAT and NL2 content of axo-axonic synapses were found to be comparable across layers in control and disease conditions. Furthermore, we did not detect any significant difference in the synaptic intensities of any of the studied GABA_AR subunits between control and schizophrenia subjects, regardless of whether the total synaptic population or layer-specific subsets were analyzed.
Our results suggest that the GABA_AR subunit composition at prefrontal axo-axonic synapses is not fundamentally altered in schizophrenia.