Immp2l knockdown in male mice increases stimulus-driven instrumental behaviour but does not alter goal-directed learning or neuron density in cortico-striatal circuits in a model of Tourette syndrome and autism spectrum disorder

Leung, Beatrice K.; Merlin, Sam; Walker, Adam K.; Lawther, Adam J.; Paxinos, George; Eapen, Valsamma; Clarke, Raymond A.; Balleine, Bernard W.; Furlong, Teri M.

doi:10.1016/j.bbr.2023.114610

Cited by 6 publications

(15 citation statements)

References 113 publications

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“…The findings in this and other studies further indicate that the Immp2l-mediated dopamine dysregulation is unlikely to be due to neurodegeneration [ 55 , 56 , 93 , 94 ]. Moreover, the EM performed on the prefrontal cortex in this study ( Figure 7 ) together with the extensive immunohistochemical investigation of other dopamine associated brain regions by Leung et al [ 55 ] does appear to confirm this hypothesis [ 55 ]. Furthermore, our investigations indicate that dexamphetamine/dopamine-mediated behaviours are most affected by the KO of Immp2l because behaviours that are far less governed by dopamine were largely unaffected, such as conditioned fear and elevated plus maze behaviour.…”

Section: Discussionsupporting

confidence: 76%

“…The genotype ratios of offspring from mating 40 homozygote x homozygote mice and 62 heterozygote x heterozygote mice indicated normal fertility and Mendelian inheritance ( Table 4 and Table 5 ). Previous behavioural testing of this Immp2l KD mouse line [ 54 , 55 ] identified behavioural differences compared with wild-type littermates with the strongest differences presenting in male Immp2l KD −/− KO mice [ 54 ].…”

Section: Resultsmentioning

confidence: 99%

“…In this investigation we found that Immp2l KD −/− KO female and male mice showed no evidence of ataxia beyond 18 months of age (see Results Section 3.1 ). Upon dissection of the brain of male and female Immp2l KD −/− KO mice (n = 30), all regions of the brain examined appeared in excellent condition with no evidence of overt neurodegeneration [ 55 ]. We used electron microscopy (EM) to interrogate high-resolution images of the medial prefrontal cortex of male adult mice for evidence of neurodegeneration.…”

Section: Resultsmentioning

confidence: 99%

“…High-resolution EM images provided no evidence of neurodegeneration in Immp2l KD −/− KO male mice ( Figure 7 A–F). More extensive immunohistochemical analyses further confirmed that there was no evidence of neurodegeneration in other dopamine related regions of the brain of Immp2l KD −/− KO male mice nor was there any reduction in neuronal number in these regions of the brain tested [ 55 ].…”

Section: Resultsmentioning

confidence: 99%

“…In our earlier studies of behaviour we observed that Immp2l KD homozygous (−/−) and heterozygous (+/−) KO mice [ 53 ] do not exhibit any of the core behavioural symptoms of ASD with no evidence of impaired social interaction, repetitive behaviours, restricted interests or behavioural rigidity [ 54 ]. Albeit Immp2l KD −/− KO mice do display increased auditory stimulus-driven instrumental behaviour [ 55 ] and enhanced drug-induced locomotion in response to dexamphetamine that is both gene-dose dependent and sex-specific [ 54 ].…”

Section: Introductionmentioning

confidence: 99%

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Antioxidant Behavioural Phenotype in the Immp2l Gene Knock-Out Mouse

Lawther,

Zieba,

Fang

et al. 2023

Genes

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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 Immp2lKD knockout (KO) mouse model which is devoid of Immp2l peptidase activity. Immp2lKD −/− KO mice do not display any of the core behavioural symptoms of ASD, albeit homozygous Immp2lKD −/− 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 Immp2lKD −/− KO mice. To our surprise, we observed that ROS levels were not increased but significantly lowered in our new Immp2lKD −/− 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 Immp2lKD −/− 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.

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