Abstract
BackgroundPeople with fragile X syndrome (FXS) often have deficits in social behavior, and a substantial portion meet criteria for autism spectrum disorder. Though the genetic cause of FXS is known to be due to the silencing of FMR1, and the Fmr1 null mouse model representing this lesion has been extensively studied, the contributions of this gene and its protein product, FMRP, to social behavior are not well understood.MethodsFmr1 null mice and wildtype littermates were exposed to a social or non-social stimulus. In one experiment, subjects were assessed for expression of the inducible transcription factor c-Fos in response to the stimulus, to detect brain regions with social-specific activity. In a separate experiment, tissue was taken from those brain regions showing differential activity, and RNA sequencing was performed.ResultsImmunohistochemistry revealed a significantly greater number of c-Fos-positive cells in the lateral amygdala and medial amygdala in the brains of mice exposed to a social stimulus, compared to a non-social stimulus. In the prelimbic cortex, there was no significant effect of social stimulus; although the number of c-Fos-positive cells was lower in the social condition compared to the non-social condition, and negatively correlated with c-Fos in the amygdala. RNA sequencing revealed differentially expressed genes enriched for molecules known to interact with FMRP and also for autism-related genes identified in the Simons Foundation Autism Research Initiative gene database. Ingenuity Pathway Analysis detected enrichment of differentially expressed genes in networks and pathways related to neuronal development, intracellular signaling, and inflammatory response.ConclusionsUsing the Fmr1 null mouse model of fragile X syndrome, we have identified brain regions, gene networks, and molecular pathways responsive to a social stimulus. These findings, and future experiments following up on the role of specific gene networks, may shed light on the neural mechanisms underlying dysregulated social behaviors in fragile X syndrome and more broadly.
Highlights
People with fragile X syndrome (FXS) often have deficits in social behavior, and a substantial portion meet criteria for autism spectrum disorder
Bonferroni post hoc analyses for staining intensity measurements indicated that the social mutant group displayed significantly greater staining intensity than all other groups in both the lateral/basolateral amygdala (LA) and the medial amygdala (MA)
Main effects for the social stimulus eliciting greater c-Fos intensity were seen across both wildtype and Fmr1 null mice in the LA (F(1,12) = 12.64, p = 0.004) and MA (F(1,12) = 28.94, p < 0.001), while main effects for the social stimulus eliciting less c-Fos intensity were seen in the prelimbic cortex (PLC) (F(1,12) = 8.11, p = 0.015)
Summary
People with fragile X syndrome (FXS) often have deficits in social behavior, and a substantial portion meet criteria for autism spectrum disorder. Fmr null mice have been a primary tool to investigate the cellular, synaptic, and molecular changes underlying FXS [21]. These mice display behavioral, structural, and molecular abnormalities that mirror some of those seen in FXS [22]. While the preponderance of evidence suggests that Fmr null mice do have changes in social behavior compared to wildtype controls, results have been inconsistent across labs and appear to be dependent on the inbred strain background of the mice being studied, with abnormalities more frequently reported on an FVB/ 129S mixed background [22,23,24,25]. In addition to abnormal social behavior, Fmr null mice have been reported to show several other behavioral deficits, including hyperactivity, attention deficits, learning deficits, and abnormal reactions to sensory stimuli [25, 44,45,46,47], these behavioral changes have been inconsistent across labs
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