Mice Lacking Brinp2 or Brinp3, or Both, Exhibit Behaviors Consistent with Neurodevelopmental Disorders

Abstract

Background: Brinps 1–3, and Astrotactins (Astn) 1 and 2, are members of the Membrane Attack Complex/Perforin (MACPF) superfamily that are predominantly expressed in the mammalian brain during development. Genetic variation at the human BRINP2/ASTN1 and BRINP1/ASTN2 loci has been implicated in neurodevelopmental disorders. We, and others, have previously shown that Brinp1−/− mice exhibit behavior reminiscent of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD).Method: We created Brinp2−/− mice and Brinp3−/− mice via the Cre-mediated LoxP system to investigate the effect of gene deletion on anatomy and behavior. Additionally, Brinp2−/−Brinp3−/− double knock-out mice were generated by interbreeding Brinp2−/− and Brinp3−/− mice. Genomic validation was carried out for each knock-out line, followed by histological, weight and behavioral examination. Brinp1−/−Brinp2−/−Brinp3−/− triple knock-out mice were also generated by crossing Brinp2/3 double knock-out mice with previously generated Brinp1−/− mice, and examined by weight and histological analysis.Results: Brinp2−/− and Brinp3−/− mice differ in their behavior: Brinp2−/− mice are hyperactive, whereas Brinp3−/− mice exhibit marked changes in anxiety-response on the elevated plus maze. Brinp3−/− mice also show evidence of altered sociability. Both Brinp2−/− and Brinp3−/− mice have normal short-term memory, olfactory responses, pre-pulse inhibition, and motor learning. The double knock-out mice show behaviors of Brinp2−/− and Brinp3−/− mice, without evidence of new or exacerbated phenotypes.Conclusion: Brinp3 is important in moderation of anxiety, with potential relevance to anxiety disorders. Brinp2 dysfunction resulting in hyperactivity may be relevant to the association of ADHD with chromosome locus 1q25.2. Brinp2−/− and Brinp3−/− genes do not compensate in the mammalian brain and likely have distinct molecular or cell-type specific functions.

Genetic Variation in the ASTN2 Locus in Cardiovascular, Metabolic and Psychiatric Traits: Evidence for Pleiotropy Rather Than Shared Biology

“…Indeed, our results agree with numerous studies demonstrating the association between mood instability and neuroticism, which is reassuring, given that mood instability has been described as a "distinctive feature of neuroticism" [46]. Prior studies have implicated this locus in determining psychiatric traits [44,45,47,48] which overlap to varying degrees with these intermediate traits, providing additional weight to the hypothesis that alterations in synaptic signalling could underpin many psychological and psychiatric phenotypes.…”

Synapse type-specific proteomic dissection identifies IgSF8 as a hippocampal CA3 microcircuit organizer

“… 82 ) and validated to be present in MF synaptosomes. Brinp2 KO mice display hyperactivity 83 , but the function of BRINP2 is not known. Finally, the transmembrane protein IgSF8 interacts with tetraspanins and integrins 84 – 86 , and is thought to modulate cell motility in immune and cancer cells through tetraspanin microdomains 87 , 88 .…”

Long-term antibiotic use during early life and risks to mental traits: an observational study and gene–environment-wide interaction study in UK Biobank cohort

“…BRINP3 is another anxiety-associated gene identified by GEWIS. Berkowicz et al [41] observed that BRINP3−/− mice altered sociability and exhibited marked changes in anxietyresponse on the elevated plus maze.…”