Df(h22q11)/+ mouse model exhibits reduced binding levels of GABAA receptors and structural and functional dysregulation in the inhibitory and excitatory networks of hippocampus

Abstract

The 22q11.2 hemizygous deletion confers high risk for multiple neurodevelopmental disorders. Inhibitory signaling, largely regulated through GABA_A receptors, is suggested to serve a multitude of brain functions that are disrupted in the 22q11.2 deletion syndrome. We investigated the putative deficit of GABA_A receptors and the potential substrates contributing to the inhibitory and excitatory dysregulations in hippocampal networks of the Df(h22q11)/+ mouse model of the 22q11.2 hemizygous deletion. The Df(h22q11)/+ mice exhibited impairments in several hippocampus-related functional domains, represented by impaired spatial memory and sensory gating functions. Autoradiography using the [³H]muscimol tracer revealed a significant reduction in GABA_A receptor binding in the CA1 and CA3 subregions, together with a loss of GAD67⁺ interneurons in CA1 of Df(h22q11)/+ mice. Furthermore, electrophysiology recordings exhibited significantly higher neuronal activity in CA3, in response to the GABA_A receptor antagonist, bicuculline, as compared with wild type mice. Density and volume of dendritic spines in pyramidal neurons were reduced and Sholl analysis also showed a reduction in the complexity of basal dendritic tree in CA1 and CA3 subregions of Df(h22q11)/+ mice. Overall, our findings demonstrate that hemizygous deletion in the 22q11.2 locus leads to dysregulations in the inhibitory circuits, involving reduced binding levels of GABA_A receptors, in addition to functional and structural modulations of the excitatory networks of hippocampus.

Keywords: 22q11.2 hemizygous deletion; GABA(A) receptors; Hippocampus; Pyramidal neurons; [(3)H]muscimol.