Evaluation of Perineuronal Nets and Their Regulation by Serotonin 5‐HT 7 Receptors in a Juvenile Fmr1 Knockout Mouse Model of Fragile X Syndrome

Abstract

Fragile X Syndrome (FXS) is the leading monogenic cause of autism and intellectual disability. Individuals with FXS also often experience several other neuropsychiatric symptoms, including seizures. FXS is caused by silencing of the FMR1 gene, preventing expression of FMRP, an RNA-binding protein that regulates protein synthesis. A widespread theory is that the lack of FMRP causes an imbalance in excitatory—inhibitory neurotransmission, leading to excessive excitatory tone, which may explain the relatively high prevalence of seizures in individuals diagnosed with FXS and autism. The central serotonin system can modulate symptoms of FXS, and certain serotonin receptors (5-HTRs) are functionally linked with proteins known to be altered in FXS, suggesting targeting them may be therapeutic for FXS. For example, reports show that activation of 5-HT7Rs increases activity of matrix metalloproteinase 9 (MMP-9), which is upregulated in the absence of FMRP; MMP-9 degrades perineuronal nets (PNNs) that form around parvalbumin-positive GABAergic interneurons, suggesting blockade of 5-HT7Rs may restore MMP-9 homeostasis, leading to enhanced inhibitory tone in FXS. The formation of PNNs coincides with the closing of juvenile plasticity. Previous studies show that PNN density in the auditory cortex is reduced in juvenile Fmr1 knockout mice, and coincident hyperexcitability of the auditory cortex may contribute to the audiogenic seizure (AGS) phenotype that is prominent in juvenile Fmr1 knockout mice. Recently, we reported that a novel serotonin receptor modulator, FPT, that has potent 5-HT7R competitive antagonist activity, completely blocks AGSs in juvenile Fmr1 knockout mice. Here we report that the selective 5-HT7R antagonist, SB-269970, reduced AGS lethality in juvenile Fmr1 knockout mice compared to vehicle, but effects were not statistically significant (P=0.21, N=12 each). Preliminary results support previous observations of reduced density of PNNs in the auditory cortex of juvenile Fmr1 knockout mice (N=8) compared to WT mice (N=8). Ongoing studies are investigating PNN density following semi-chronic administration of SB-269970 or FPT to determine the efficacy of 5-HT7R blockade or other pharmacological mechanisms of FPT to normalize PNN density in juvenile Fmr1 knockout mice to wild-type mice levels.