Characterization of the behavioral phenotype and neuroinflammatory profile of the Fmr1 knockout mouse

Abstract

Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by a variety of behavioral, intellectual, and physiological abnormalities. It is caused by an expanded trinucleotide (CGG) repeat in the FMR1 gene, leading to hypermethylation and functional silencing of expression of fragile X mental retardation protein (FMRP). In this current study, we examined social behavior, anxiety, locomotor activity, repetitive behavior, learning and memory, and ultrasonic vocalizations (USVs) in adult male Fmr1 knockout (KO) and wild type (WT) mice on a FVB background strain. In comparison to WT mice, Fmr1 KO mice had significant increases in activity levels, as well as decreased anxiety and deficits in learning/memory. There were no differences detected in repetitive behavior and sociability between genotypes. The syndrome is also characterized by deficits in communication such as impairments in conversational speech, perseveration of words, and stuttering-like repetition of sounds. We utilized a female urine-induced paradigm to examine USVs and found extensive qualitative differences in vocalizations between Fmr1 KO and WT mice. There has been increasing evidence in both humans and mouse models suggesting dysregulated microglia activity and cytokine production to be associated with the pathogenesis of FXS, as well as evidence of anti-inflammatory agents having an effect on vocalization behavior. Thus, we also examined the hippocampal expression of key cytokines to determine whether an abnormal immune profile may be linked to the behavioral deficits.