Antioxidant Behavioural Phenotype in the Immp2l Gene Knock-Out Mouse

Adam J Lawther; Jerzy Zieba; Zhiming Fang; Teri M Furlong; Illya Conn; Hemna Govindaraju; Laura L Y Choong; Nigel Turner; Khawar Sohail Siddiqui; Wallace Bridge; Sam Merlin; Tzipi Cohen Hyams; Murray Killingsworth; Valsamma Eapen; Raymond A Clarke; Adam K Walker

doi:10.3390/genes14091717

Antioxidant Behavioural Phenotype in the Immp2l Gene Knock-Out Mouse

Genes (Basel). 2023 Aug 28;14(9):1717. doi: 10.3390/genes14091717.

Authors

Adam J Lawther¹, Jerzy Zieba^{1

2}, Zhiming Fang^{3

4}, Teri M Furlong⁵, Illya Conn^{1

6}, Hemna Govindaraju^{7

8}, Laura L Y Choong^{7

8}, Nigel Turner^{7

8}, Khawar Sohail Siddiqui⁹, Wallace Bridge⁹, Sam Merlin¹⁰, Tzipi Cohen Hyams⁴, Murray Killingsworth^{4

11}, Valsamma Eapen^{3

4

12}, Raymond A Clarke^{3

4

12}, Adam K Walker^{1

3

13}

Affiliations

¹ Laboratory of ImmunoPsychiatry, Neuroscience Research Australia, Randwick, NSW 2031, Australia.
² Department of Psychology, University of Rzeszow, 35-310 Rzeszow, Poland.
³ Discipline of Psychiatry and Mental Health, University of New South Wales, Sydney, NSW 2052, Australia.
⁴ Ingham Institute for Applied Medical Research, Sydney, NSW 2170, Australia.
⁵ School of Biomedical Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
⁶ Schizophrenia Research Laboratory, Neuroscience Research Australia, Randwick, NSW 2031, Australia.
⁷ Department of Pharmacology, School of Biomedical Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
⁸ Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia.
⁹ School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
¹⁰ Medical Science, School of Science, Western Sydney University, Campbelltown, Sydney, NSW 2751, Australia.
¹¹ NSW Health Pathology, Liverpool Hospital Campus, 1 Campbell Street, Liverpool, NSW 2107, Australia.
¹² Academic Unit of Infant Child and Adolescent Services (AUCS), South Western Sydney Local Health District, Liverpool, NSW 2170, Australia.
¹³ Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.

Abstract

Mitochondrial dysfunction is strongly associated with autism spectrum disorder (ASD) and the Inner mitochondrial membrane protein 2-like (IMMP2L) gene is linked to autism inheritance. However, the biological basis of this linkage is unknown notwithstanding independent reports of oxidative stress in association with both IMMP2L and ASD. To better understand IMMP2L's association with behaviour, we developed the Immp2l^KD knockout (KO) mouse model which is devoid of Immp2l peptidase activity. Immp2l^KD -/- KO mice do not display any of the core behavioural symptoms of ASD, albeit homozygous Immp2l^KD -/- KO mice do display increased auditory stimulus-driven instrumental behaviour and increased amphetamine-induced locomotion. Due to reports of increased ROS and oxidative stress phenotypes in an earlier truncated Immp2l mouse model resulting from an intragenic deletion within Immp2l, we tested whether high doses of the synthetic mitochondrial targeted antioxidant (MitoQ) could reverse or moderate the behavioural changes in Immp2l^KD -/- KO mice. To our surprise, we observed that ROS levels were not increased but significantly lowered in our new Immp2l^KD -/- KO mice and that these mice had no oxidative stress-associated phenotypes and were fully fertile with no age-related ataxia or neurodegeneration as ascertained using electron microscopy. Furthermore, the antioxidant MitoQ had no effect on the increased amphetamine-induced locomotion of these mice. Together, these findings indicate that the behavioural changes in Immp2l^KD -/- KO mice are associated with an antioxidant-like phenotype with lowered and not increased levels of ROS and no oxidative stress-related phenotypes. This suggested that treatments with antioxidants are unlikely to be effective in treating behaviours directly resulting from the loss of Immp2l/IMMP2L activity, while any behavioural deficits that maybe associated with IMMP2L intragenic deletion-associated truncations have yet to be determined.

Keywords: AlphaFold; Autism; GPD2; IMMP2L; Immp1l; MitoQ; Tourette’s syndrome; amphetamine; antioxidant; behaviour; dopamine; heterodimer; locomotion; oxidative stress.

Publication types

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

MeSH terms

Amphetamine
Animals
Antioxidants* / pharmacology
Autism Spectrum Disorder*
Membrane Proteins / genetics
Mice
Mice, Knockout
Phenotype
Reactive Oxygen Species

Substances

Amphetamine
Antioxidants
Membrane Proteins
Reactive Oxygen Species
inner mitochondrial membrane peptidase 2-like protein, mouse

Grants and funding

This research was funded as by a Sydney Partnership for Health Education Research and Enterprise (SPHERE) Grant to AKW, VE, RC, TF, SM and JZ. AKW is supported by a National Breast Cancer Foundation Australia (PF-15-014), the Schizophrenia Research Institute, UNSW, Australia, and Neuroscience Research Australia, NSW, Australia. HG and LLYC are supported by Australian Government Research Training Program Scholarships.