Gabrb2 knockout mice displayed schizophrenia-like and comorbid phenotypes with GABAergic interneuron-astrocyte-microglia dysregulation and neuroinflammation

Abstract

Intronic polymorphisms of the GABA_A receptor β₂ subunit gene (GABRB2) were earlier associated with schizophrenia, deficit of gene expression, different electrophysiological properties of the long and short isoforms, and identification of both preventive and causative haplotypes. Herein, gene dosage effects of Gabrb2 were examined in knockout mice of both heterozygous (HT) and homozygous (KO) genotypes. Gabrb2-knockout HT and KO mice were evaluated for schizophrenia-like phenotypes and comorbidities employing animal behavioral tests. Neural alterations in these mice were studied using biochemical and immunohistochemical assays. The KO mice, and HT mice to a lesser extent, were found to display prepulse inhibition deficit, locomotor hyperactivity, stereotypy, sociability impairments, spatial-working and spatial-reference memory deficits, reduced depression and anxiety, and accelerated pentylenetetrazol-induced seizure. In addition, the KO mice were highly susceptible to audiogenic epilepsy. Some of the schizophrenia-like phenotypes and comorbidities showed evidence of imprinting, gender effect and amelioration by the antipsychotic risperidone, whereas the audiogenic epilepsy was inhibited by the antiepileptic diazepam. GABAergic parvalbumin-positive interneuron dystrophy, astrocyte dystrophy and extensive microglia activation were observed in the frontotemporal corticolimbic regions, and reduction of newborn neurons was observed in the hippocampus by immunohistochemical staining. The neuroinflammation suggested by microglial activation was also indicated by elevated brain levels of oxidative stress marker malondialdehyde and the pro-inflammatory cytokines tumor necrosis factor-alpha and interleukin-6. The extensive schizophrenia-like phenotypes and comorbidities brought about by Gabrb2 knockout, in conjunction with our previous findings on GABRB2 association with schizophrenia, provided evidence for a GABRB2-origin hypothesis of schizophrenia.

Date of Award	2018
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology