Differences in Neuronal Activation and Gene Expression in the Fragile X Mouse

Background:  Abnormal social behavior is a core symptom of autism spectrum disorders (ASD) and fragile X syndrome (FXS). Interestingly, previous studies have demonstrated an association of amygdala activation with both social approach and social avoidance behavior. Further, both functional and structural neuroimaging studies have implicated the amygdala and PFC in ASD. It is currently unclear whether molecular changes occurring in the amygdala and PFC could mediate altered social behavior observed in ASD and FXS. We used the Fmr1 knockout (KO) mouse, which displays altered social behavior, to further investigate this relationship.

Objectives:  1) Determine the impact of a loss of Fmr1 expression on neuronal activation patterns in amygdala and PFC following exposure to a social stimulus. 2) Identify gene expression changes in the amygdala and PFC of Fmr1 KO mice in response to social challenge.

Methods:  Fmr1 KO mice and littermate controls were exposed to a behavioral challenge that parallels the 3-chamber sociability test but separates the exposures so that a subject mouse encounters either a novel mouse or a novel object. We used immediate early gene activation (cFos) immunohistochemistry and compared neuronal activation patterns in different brain regions across conditions and genotypes. RNA sequencing of the lateral amygdala, medial amygdala, and PFC in each condition and genotype is underway.

Results:  Presentation of a novel mouse, as compared to the presentation of a novel item, elicited increased levels of activation in the lateral and medial amygdala and decreased levels of activation in the PFC in wildtype animals (p < .05). Fmr1 KO mice displayed increased neuronal activation in lateral and medial amygdala across both behavioral conditions as compared to littermate controls (p < .01). Also, Fmr1 KO mice displayed decreased activation of PFC across both behavioral conditions as compared to littermate controls (p < .05). RNA sequencing results will also be presented.

Conclusions:  The current findings indicate that both the amygdala and the PFC display differences in neuronal activation patterns in response to social stimuli in comparison to non-social stimuli. Fmr1 KO mice display exaggerated responses in both brain areas that could underlie altered social behaviors. Differences in gene expression in these two brain areas in response to social challenge may suggest a mechanism for the changes in neuronal activation patterns and behavioral responses.