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Neuroanatomical and Behavioral Deficits in Mice Haploinsufficient for Pericentriolar Material 1 (Pcm1)

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Neuroanatomical and Behavioral Deficits in Mice Haploinsufficient for Pericentriolar Material 1 (Pcm1)

Sandra Zoubovsky et al. Neurosci Res.

Abstract

The pericentriolar material (PCM) is composed of proteins responsible for microtubule nucleation/anchoring at the centrosome, some of which have been associated with genetic susceptibility to schizophrenia. Here, we show that mice haploinsufficient for Pericentriolar material 1 (Pcm1(+/-)), which encodes a component of the PCM found to bear rare loss of function mutations in patients with psychiatric illness, manifest neuroanatomical phenotypes and behavioral abnormalities. Using ex vivo magnetic resonance imaging of the Pcm1(+/-) brain, we detect reduced whole brain volume. Pcm1 mutant mice show impairment in social interaction, specifically in the social novelty phase, but not in the sociability phase of the three-chamber social interaction test. In contrast, Pcm1(+/-) mice show normal preference for a novel object, suggesting specific impairment in response to novel social stimulus. In addition, Pcm1(+/-) mice display significantly reduced rearing activity in the open field. Pcm1(+/-) mice behave normally in the elevated plus maze, rotarod, prepulse inhibition, and progressive ratio tests. Together, our results suggest that haploinsufficiency at the Pcm1 locus can induce a range of neuroanatomical and behavioral phenotypes that support the candidacy of this locus in neuropsychiatric disorders.

Keywords: Behavior; Mouse model; Neuroanatomy; Pcm1; Schizophrenia.

Conflict of interest statement

Conflict of interest statement

There are no known conflicts of interest for any author.

Figures

Fig. 1
Fig. 1
Immunoblot to demonstrate haploinsufficiency in Pcm1+/− mice (A) and gross brain anatomy by structural magnetic resonance imaging at 4 months of age (B). Whole brain volume of Pcm1+/− mice was reduced significantly compared to WT mice, *p<0.05. No significant differences in the relative volumes (out of whole brain volume) of the other regions of interest were observed in Pcm1+/− brains.
Fig. 2
Fig. 2
Pcm1+/− mice were impaired in recognition of a novel social stimulus, but not a novel object. (A) No difference in locomotion in the open field (left). Pcm1+/− mice stopped habituating at 80 min, ttest comparing 80 min vs. 120 min: p<0.01 for WT, p=0.85 for Pcm1+/− mice (right). (B) Pcm1+/− mice reared less in the open field, *p<0.05. (C) No change in measurements of anxiety based on % center activity in the open field (left) and % time in the open arms of the elevated plus (right). (D) In the novel object recognition test, Pcm1+/− mice showed normal preference for the novel object after a 1 h inter-trial interval. Presented as interaction with novel object/total interaction time. (E) The three-chamber social interaction test. In the sociability phase only WT mice interacted more with the mouse than with an empty enclosure (p<0.05), but ANOVA did not detect a significant effect of Pcm1+/− on sociability (left). In the social novelty phase the Pcm1+/− mice were impaired, F(1,25)=12.38, **p<0.01 (right). WT mice interacted both with the familiar and with the novel mouse significantly longer than the Pcm1+/− mice interacted with each (Bonferroni post-test analysis, p<0.001).
Fig. 3
Fig. 3
Normal motor and reinforcement behavioral responses in Pcm1+/− mice. (A) Similar rotarod performance was observed between Pcm1+/− and WT littermates. (B) Sensorimotor gating of acoustic startle: Pcm1+/− mice had reduced startle response (left, p*<0.05), but normal prepulse inhibition, right). (C) Progressive ratio test: Pcm1+/− mice earned the same amount of sucrose indicating that they were as willing as WT mice to work for a reward.

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