A research group led by Hong Xue at Hong Kong University of Science and Technology, unveiled resources & recommendations that propose a new approach for investigator qualification — “analyzing the gene dosage impacts of GABAA receptor β2 subunit gene (Gabrb2) in knockout mice of both heterozygous (HT) and homozygous (KO) genotypes concerning possible schizophrenia-like and comorbid phenotypes with microglia-dysregulation — a medical study that goes beyond repetitive training and includes individual experience and protocol-particulate preparation.
Schizophrenia is a multi-factorial disease that is caused not by a single gene mutation, but reciprocation of combination of genetic and environmental elements. The sturdiness of genetic factors is marked by the rise of lifetime risk of the disease from just below 1% in general population to over 40% in monozygotic twin studies, leading to author–Hong’s extensive searches for the genetic basis of the disease.
Currently, neural elements that are identified to play crucial roles in schizophrenia include contribution of debilitated dopaminergic neurotransmission to the genesis of psychotic symptoms and deformities of neuronal kinship likely involving interneuron.
The corresponding author says, with the advent of unrivalled tools, such as next-generation sequencing and huge data analytics, we are in a state to rapidly determine and compare the genomic changes and genetic differences peculiar to any individual of our species. Such genomic perspectives not just enable us to have an insight into the genetics of complex disease but also address queries concerning clinical outcomes among the patients. Taking this approach into consideration, Hong incorporated Gabrb2 heterozygous (HT) transgenic mice that were bred to produce HT, wild-type (WT), and knockout (KO) mice that were weaned, genotyped using particular primers for the Gabrb2 and Neo genes (Supplementary Techniques) with water and food ad lib.
Conducted in compliance with The Code of Practice for Care and Use of Animals for Experimental Purposes, the study directed to assess the gene dosage effects of Gabrb2 in (HT) (KO) mice genotypes — displayed deficiency of prepulse inhibition (PPI) to a significantly lesser extent in both the mice. Further the findings from the research showed reduced anxiety and depression, sociability afflictions, locomotor hyperactivity, spatial-operating and spatial-reference memory deficits, and escalated pentylenetetrazol (PTZ)-influenced seizure.
Additionally, the KO mice were reported to be highly defenseless against audiogenic epilepsy. To further examine, the author used male mice, (8–10 weeks) old that were incorporated in the behavioral tests besides social behavior which incorporated 9–10-weeks-old female mice. Both genders were implemented in the epilepsy tests, also including 3-weeks-old mice, based on previous protocols (Supplementary Techniques). To monitor fertility in 8-week-old mice and assessing parent-of-origin effects, Paternal HT-P and Maternal HT-M mice were engendered by mating KO male with WT female and WT male with KO female, respectively. The study showed compromised fertility in naive KO mice compared to WT mice, with p < 0.05. The authors through their study sought out that some of the behavioral phenotypes support the pivotal role played by GABRB2 in schizophrenia etiology and comorbid phenotypes.
Further, when the anxiety & depression levels of KO and HT mice were put to examination, it revealed the KO mice to have had noticeably reduced immobility time in the tail-suspension test and also elevated sucrose preference compared to WT mice. While, the HT mice showed just about little reduction in tail-suspension time and no noticeable increase in sucrose preference. Thus KO, and minimally HT, revealed reduced level of anxiety comparative to WT.
Moreover, there were remarkable changes observed in the brain of KO mice. By immuno-histochemical staining, the authors have revealed extensive parvalbumin-positive interneuron and astrocyte dystrophy in important brain regions such as hippocampus in KO mice. Over activation of microglia, a scavenger type of cells, shown by immuno-histochemical staining, together with enhanced oxidation stress and inflammatory factors, shown by biochemical assays, has demonstrated extensive neuro-inflammation in the KO mice. Thereby, their study has established GABRB2 as a key player in schizophrenia and comorbid disorders, and hence opens up a new avenue for therapeutic intervention of such debilitating mental disorders.