Brinp1-/- mice exhibit autism-like behaviour, altered memory, hyperactivity and increased parvalbumin-positive cortical interneuron density

Susan R. Berkowicz, Travis J. Featherby, Zhengdong Qu, Aminah Giousoh, Natalie A. Borg, Julian I. Heng, James C. Whisstock, Phillip I. Bird

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background: BMP/RA-inducible neural-specific protein 1 (Brinp1) is highly conserved in vertebrates, and continuously expressed in the neocortex, hippocampus, olfactory bulb and cerebellum from mid-embryonic development through to adulthood. Methods: Brinp1 knock-out (Brinp1-/-) mice were generated by Cre-recombinase-mediated removal of the third exon of Brinp1. Knock-out mice were characterised by behavioural phenotyping, immunohistochemistry and expression analysis of the developing and adult brain. Results: Absence of Brinp1 during development results in a behavioural phenotype resembling autism spectrum disorder (ASD), in which knock-out mice show reduced sociability and changes in vocalisation capacity. In addition, Brinp1-/- mice exhibit hyper-locomotor activity, have impaired short-term memory, and exhibit poor reproductive success. Brinp1-/- mice show increased density of parvalbumin-expressing interneurons in the adult mouse brain. Brinp1-/- mice do not show signs of altered neural precursor proliferation or increased apoptosis during late embryonic brain development. The expression of the related neuronal migration genes Astn1 and Astn2 is increased in the brains of Brinp1-/- mice, suggesting that they may ameliorate the effects of Brinp1 loss. Conclusions: Brinp1 plays an important role in normal brain development and function by influencing neuronal distribution within the cortex. The increased cortical PV-positive interneuron density and altered behaviour of Brinp1-/- mice resemble features of a subset of human neurological disorders; namely autism spectrum disorder (ASD) and the hyperactivity aspect of attention deficit hyperactivity disorder (ADHD).
Original languageEnglish
Number of pages20
JournalMolecular Autism
Volume7
Issue number22
DOIs
Publication statusPublished - 31 Mar 2016

Keywords

  • Brinp1
  • knock-out
  • cortex
  • parvalbumin
  • interneuron
  • neurodevelopment
  • autism spectrum disorder
  • hyperactivity

Cite this

@article{e15963c784d34dadbd705c6e18408088,
title = "Brinp1-/- mice exhibit autism-like behaviour, altered memory, hyperactivity and increased parvalbumin-positive cortical interneuron density",
abstract = "Background: BMP/RA-inducible neural-specific protein 1 (Brinp1) is highly conserved in vertebrates, and continuously expressed in the neocortex, hippocampus, olfactory bulb and cerebellum from mid-embryonic development through to adulthood. Methods: Brinp1 knock-out (Brinp1-/-) mice were generated by Cre-recombinase-mediated removal of the third exon of Brinp1. Knock-out mice were characterised by behavioural phenotyping, immunohistochemistry and expression analysis of the developing and adult brain. Results: Absence of Brinp1 during development results in a behavioural phenotype resembling autism spectrum disorder (ASD), in which knock-out mice show reduced sociability and changes in vocalisation capacity. In addition, Brinp1-/- mice exhibit hyper-locomotor activity, have impaired short-term memory, and exhibit poor reproductive success. Brinp1-/- mice show increased density of parvalbumin-expressing interneurons in the adult mouse brain. Brinp1-/- mice do not show signs of altered neural precursor proliferation or increased apoptosis during late embryonic brain development. The expression of the related neuronal migration genes Astn1 and Astn2 is increased in the brains of Brinp1-/- mice, suggesting that they may ameliorate the effects of Brinp1 loss. Conclusions: Brinp1 plays an important role in normal brain development and function by influencing neuronal distribution within the cortex. The increased cortical PV-positive interneuron density and altered behaviour of Brinp1-/- mice resemble features of a subset of human neurological disorders; namely autism spectrum disorder (ASD) and the hyperactivity aspect of attention deficit hyperactivity disorder (ADHD).",
keywords = "Brinp1, knock-out, cortex, parvalbumin, interneuron, neurodevelopment, autism spectrum disorder, hyperactivity",
author = "Berkowicz, {Susan R.} and Featherby, {Travis J.} and Zhengdong Qu and Aminah Giousoh and Borg, {Natalie A.} and Heng, {Julian I.} and Whisstock, {James C.} and Bird, {Phillip I.}",
year = "2016",
month = "3",
day = "31",
doi = "10.1186/s13229-016-0079-7",
language = "English",
volume = "7",
journal = "Molecular Autism",
issn = "2040-2392",
publisher = "Springer-Verlag London Ltd.",
number = "22",

}

Brinp1-/- mice exhibit autism-like behaviour, altered memory, hyperactivity and increased parvalbumin-positive cortical interneuron density. / Berkowicz, Susan R.; Featherby, Travis J.; Qu, Zhengdong; Giousoh, Aminah; Borg, Natalie A.; Heng, Julian I.; Whisstock, James C.; Bird, Phillip I.

In: Molecular Autism, Vol. 7, No. 22, 31.03.2016.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Brinp1-/- mice exhibit autism-like behaviour, altered memory, hyperactivity and increased parvalbumin-positive cortical interneuron density

AU - Berkowicz, Susan R.

AU - Featherby, Travis J.

AU - Qu, Zhengdong

AU - Giousoh, Aminah

AU - Borg, Natalie A.

AU - Heng, Julian I.

AU - Whisstock, James C.

AU - Bird, Phillip I.

PY - 2016/3/31

Y1 - 2016/3/31

N2 - Background: BMP/RA-inducible neural-specific protein 1 (Brinp1) is highly conserved in vertebrates, and continuously expressed in the neocortex, hippocampus, olfactory bulb and cerebellum from mid-embryonic development through to adulthood. Methods: Brinp1 knock-out (Brinp1-/-) mice were generated by Cre-recombinase-mediated removal of the third exon of Brinp1. Knock-out mice were characterised by behavioural phenotyping, immunohistochemistry and expression analysis of the developing and adult brain. Results: Absence of Brinp1 during development results in a behavioural phenotype resembling autism spectrum disorder (ASD), in which knock-out mice show reduced sociability and changes in vocalisation capacity. In addition, Brinp1-/- mice exhibit hyper-locomotor activity, have impaired short-term memory, and exhibit poor reproductive success. Brinp1-/- mice show increased density of parvalbumin-expressing interneurons in the adult mouse brain. Brinp1-/- mice do not show signs of altered neural precursor proliferation or increased apoptosis during late embryonic brain development. The expression of the related neuronal migration genes Astn1 and Astn2 is increased in the brains of Brinp1-/- mice, suggesting that they may ameliorate the effects of Brinp1 loss. Conclusions: Brinp1 plays an important role in normal brain development and function by influencing neuronal distribution within the cortex. The increased cortical PV-positive interneuron density and altered behaviour of Brinp1-/- mice resemble features of a subset of human neurological disorders; namely autism spectrum disorder (ASD) and the hyperactivity aspect of attention deficit hyperactivity disorder (ADHD).

AB - Background: BMP/RA-inducible neural-specific protein 1 (Brinp1) is highly conserved in vertebrates, and continuously expressed in the neocortex, hippocampus, olfactory bulb and cerebellum from mid-embryonic development through to adulthood. Methods: Brinp1 knock-out (Brinp1-/-) mice were generated by Cre-recombinase-mediated removal of the third exon of Brinp1. Knock-out mice were characterised by behavioural phenotyping, immunohistochemistry and expression analysis of the developing and adult brain. Results: Absence of Brinp1 during development results in a behavioural phenotype resembling autism spectrum disorder (ASD), in which knock-out mice show reduced sociability and changes in vocalisation capacity. In addition, Brinp1-/- mice exhibit hyper-locomotor activity, have impaired short-term memory, and exhibit poor reproductive success. Brinp1-/- mice show increased density of parvalbumin-expressing interneurons in the adult mouse brain. Brinp1-/- mice do not show signs of altered neural precursor proliferation or increased apoptosis during late embryonic brain development. The expression of the related neuronal migration genes Astn1 and Astn2 is increased in the brains of Brinp1-/- mice, suggesting that they may ameliorate the effects of Brinp1 loss. Conclusions: Brinp1 plays an important role in normal brain development and function by influencing neuronal distribution within the cortex. The increased cortical PV-positive interneuron density and altered behaviour of Brinp1-/- mice resemble features of a subset of human neurological disorders; namely autism spectrum disorder (ASD) and the hyperactivity aspect of attention deficit hyperactivity disorder (ADHD).

KW - Brinp1

KW - knock-out

KW - cortex

KW - parvalbumin

KW - interneuron

KW - neurodevelopment

KW - autism spectrum disorder

KW - hyperactivity

UR - http://www.ncbi.nlm.nih.gov/pubmed/27042284

U2 - 10.1186/s13229-016-0079-7

DO - 10.1186/s13229-016-0079-7

M3 - Article

VL - 7

JO - Molecular Autism

JF - Molecular Autism

SN - 2040-2392

IS - 22

ER -