Non-motor Behavioral Alterations of PGC-1α-Deficient Mice – A Peculiar Phenotype With Slight Male Preponderance and No Apparent Progression

Abstract

Dysfunction of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1α) has been linked to various neurodegenerative and neuropsychiatric disorders; however, reports on psychic behavioral alterations on PGC-1α-deficient animals are sparse. The present study revisited prior observations of anxiety-related, depression-related, and hippocampal memory-related observations having been made on different PGC-1α-deficient murine strains, in a large-scale analysis on whole-body full-length (FL-)PGC-1α-deficient mice. The examinations were performed on animals covering a wide age range enrolled from both sexes, and included paradigms such as the open-field, elevated plus maze, light-dark box, tail suspension test, and spatial recognition two-trial Y-maze. The findings revealed no signs of previously reported anxiety-like behavior, but revealed an unexpected phenotype with decreased anxiety behavior consistent throughout different paradigms, with slight male preponderance. This was associated with despair-like anhedonic behavior, consistent with that reported previously, but did not associate with either peripheral or brain alterations in kynurenic acid synthesis, which was previously proposed. Though male FL-PGC-1α-deficient mice tended to perform poorer in the hippocampus-based spatial learning paradigm, the genotype overall was not associated with impairment in spatial memory, contradicting with prior observations. None of the observed alterations deteriorated with age, similarly to motor alterations as reported previously. The most likely contributors of this peculiar phenotype are discussed, with clinicopathological correlations drawn. Being the first to address these behavioral domains within the same PGC-1α-deficient strain, our findings extend the knowledge about the complex in vivo effect of PGC-1α dysfunction and add important notes to research in the field of PGC-1α in connection with neuropsychiatric disorders.

Mutations on a novel brain-specific isoform of PGC1α leads to extensive upregulation of neurotransmitter-related genes and sexually dimorphic motor deficits in mice

“…3H), which may be indicative of increased anxiety and impaired swimming-related motor coordination, respectively. Interestingly, conflicting findings have been reported on anxiety-like behaviours for the full body exon 3 deletion alleles (Leone et al, 2005;Szalardy et al, 2018). Finally, we found that female, but not male SINE KO homozygous mutants, had significantly higher target quadrant preferences relative to control animals in the Morris water maze ( Fig.…”

“…Behavioural changes including hyperactivity and severe impaired motor coordination in the rotarod test were associated with the brain lesions found in the exon 3 deletion alleles (Lucas et al, 2012). However, more recent studies found less severe behavioural abnormalities in brainspecific conditional alleles of the exon 3 that were deemed to be unrelated to the neuropathology (Szalardy et al, 2016a;Szalardy et al, 2018). The extent to which the SSR-SINE-exon2 isoform contributes to these phenotypes is unknown.…”

A brain-specific pgc1α fusion transcript affects gene expression and behavioural outcomes in mice

“…Why the SINE KO animals can rapidly overcome the initial swim speed deficits is unclear. Interestingly, conflicting findings have been reported on anxiety-like behaviours for the full body exon 3 deletion alleles that retain an N-terminal truncated transcript (Leone et al, 2005;Szalardy et al, 2018). Finally, we found that female, but not male SINE KO homozygous mutants, had significantly higher target quadrant preferences relative to control animals in the Morris water maze (Fig 2G), suggesting improved spatial learning and memory (Vorhees & Williams, 2014).…”

Multiple Roles in Neuroprotection for the Exercise Derived Myokine Irisin

“…This is relevant considering different studies showing that exercise can reduce anxiety (reviewed in Anderson and Shivakumar, 2013). Furthermore, PGC-1α and BDNF levels have also been altered in rodents with anxiety-like behavior (Govindarajan et al, 2006;Szalardy et al, 2018), and both PGC-1α and BDNF can have anxiolytic properties (Agrawal et al, 2014;Xie et al, 2019). Exercise also reduces panic disorder, which is a type of anxiety disorder, through increasing BDNF concentration in serum (Strohle et al, 2010).…”