First behavioural assessment of a novel Immp2l knockdown mouse model with relevance for Gilles de la Tourette syndrome and Autism spectrum disorder

Fabian Kreilaus; Rose Chesworth; Valsamma Eapen; Raymond Clarke; Tim Karl

doi:10.1016/j.bbr.2019.112057

First behavioural assessment of a novel Immp2l knockdown mouse model with relevance for Gilles de la Tourette syndrome and Autism spectrum disorder

Behav Brain Res. 2019 Nov 18:374:112057. doi: 10.1016/j.bbr.2019.112057. Epub 2019 Jun 21.

Authors

Fabian Kreilaus¹, Rose Chesworth¹, Valsamma Eapen², Raymond Clarke³, Tim Karl⁴

Affiliations

¹ School of Medicine, Western Sydney University, NSW 2560, Australia.
² School of Psychiatry, Faculty of Medicine and Ingham Institute, University of New South Wales, NSW, 2052, Australia.
³ School of Psychiatry, Faculty of Medicine and Ingham Institute, University of New South Wales, NSW, 2052, Australia. Electronic address: r.clarke@unsw.edu.au.
⁴ School of Medicine, Western Sydney University, NSW 2560, Australia; Neuroscience Research Australia (NeuRA), NSW, 2031, Australia; School of Medical Sciences, University of New South Wales, NSW, 2052, Australia. Electronic address: t.karl@westernsydney.edu.au.

PMID: 31233820
DOI: 10.1016/j.bbr.2019.112057

Abstract

Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder, which shares some clinical features with Autism spectrum disorder (ASD). The genetic factors relevant to the development of both disorders are yet to be fully understood, however, some genetic association studies have identified inner mitochondrial membrane peptidase subunit 2 (IMMP2L) as a potential risk gene for both GTS and ASD. The impact of Immp2l deficiency on behavioural domains is currently unknown. A new genetic mouse model for Immp2l was developed. Adult heterozygous (HET) and homozygous (HOMO) Immp2l knockdown (Immp2l KD) mice of both sexes were compared to wild type-like (WT) littermates in the open field (OF), social interaction, novel object recognition, marble burying, and prepulse inhibition (PPI). The effect of acute dexamphetamine (2 mg/kg) on OF behaviour was also determined. OF locomotion was significantly higher in HET compared to HOMO male littermates. Male and female HOMO mice were much more sensitive to the locomotor-stimulating effects of dexamphetamine (DEX), whereas only HOMO males exhibited significant increased DEX-induced OF exploration compared to control groups. HOMO females failed to habituate to an acoustic startle stimulus. Furthermore, compared to HOMO females, HET females showed reduced social interaction, and a similar trend was seen in HET males. The Immp2l KD mouse model possesses moderate face validity for preclinical research into GTS and ASD, in particular as dysfunctional dopaminergic neurotransmission appears to be one mechanism leading to disease presentation. The sex-dependent differences observed in most findings reinforce the strong influence of sex in the pathophysiology of GTS and ASD.

Keywords: Autism spectrum disorders; Behaviour; Dexamphetamine; Gilles de la Tourette syndrome; Immp2l; Mouse model; Sex-dependent phenotype.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autism Spectrum Disorder / metabolism*
Behavior Rating Scale
Disease Models, Animal
Endopeptidases / genetics
Endopeptidases / metabolism*
Female
Genetic Predisposition to Disease / genetics
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondrial Proteins / genetics
Mitochondrial Proteins / metabolism*
Neurodevelopmental Disorders / genetics
Tourette Syndrome / metabolism*

Substances

Mitochondrial Proteins
Endopeptidases
IMMP2L protein, human
inner mitochondrial membrane peptidase 2-like protein, mouse