Mice LackingBrinp2orBrinp3, or Both, Exhibit Behaviors Consistent with Neurodevelopmental Disorders.
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 humanBRINP2/ASTN1andBRINP1/ASTN2loci has been implicated in neurodevelopmental disorders. We, and others, have previously shown thatBrinp1-/-mice exhibit behavior reminiscent of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD).Method:We createdBrinp2-/-mice andBrinp3-/-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 interbreedingBrinp2-/-andBrinp3-/-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 crossingBrinp2/3double knock-out mice with previously generatedBrinp1-/-mice, and examined by weight and histological analysis.Results:Brinp2-/-andBrinp3-/-mice differ in their behavior:Brinp2-/-mice are hyperactive, whereasBrinp3-/-mice exhibit marked changes in anxiety-response on the elevated plus maze.Brinp3-/-mice also show evidence of altered sociability. BothBrinp2-/-andBrinp3-/-mice have normal short-term memory, olfactory responses, pre-pulse inhibition, and motor learning. The double knock-out mice show behaviors ofBrinp2-/-andBrinp3-/-mice, without evidence of new or exacerbated phenotypes.Conclusion:Brinp3is important in moderation of anxiety, with potential relevance to anxiety disorders.Brinp2dysfunction resulting in hyperactivity may be relevant to the association of ADHD with chromosome locus 1q25.2.Brinp2-/-andBrinp3-/-genes do not compensate in the mammalian brain and likely have distinct molecular or cell-type specific functions.
Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University Clayton, VIC, Australia.
Susan R
SR
Berkowicz
Melbourne Brain Centre, Florey Neuroscience Institute Parkville, VIC, Australia.
Travis J
TJ
Featherby
Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash UniversityClayton, VIC, Australia; ARC Centre of Excellence in Advanced Molecular Imaging, Monash UniversityClayton, VIC, Australia.
James C
JC
Whisstock
Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University Clayton, VIC, Australia.
Phillip I
PI
Bird
ADHD; Brinp2; Brinp3; anxiety; knock-out mice; neurodevelopmental disorders