Targeting 5‐HT1A Receptors to Correct Perineuronal Net and Social Behavioral Deficits in Fmr1 Knockout Mice, a Model of Fragile X Syndrome

Abstract

Fragile X syndrome (FXS), caused by FMR1gene silencing and subsequent loss of the RNA‐binding protein FMRP, is the leading monogenic cause of intellectual disability and autism spectrum disorder, characterized by social deficits and repetitive behaviors. Currently, there are no approved medications for FXS. MMP‐9 is an extracellular matrix regulating enzyme and a significant target of FMRP—the loss of FMRP in FXS leads to overexpression of MMP‐9. MMP‐9 degrades perineuronal nets (PNNs) that stabilize glutamatergic and GABAergic neurotransmission, and imbalance in these neurotransmitter systems is a hallmark of FXS, suggesting correcting MMP‐9 overactivity may restore neuronal homeostasis in FXS by normalizing PNNs. For example, we show significantly decreased PNN density in hippocampal CA2 in juvenile Fmr1 knockout (KO) mice, a neural system critical for social memory, compared to wild‐type (WT) mice (P=0.0043, N=8 and 7, respectively). In parallel with PNN deficits, we show that juvenile Fmr1KO mice have social memory impairments compared to WT mice. Juvenile Fmr1 KO mice have no preference for interacting with novel mice than familiar mice (number of interactions, P=0.54; amount of time interacting, P=0.27; N=10). In contrast, WT mice interact more frequently and spend more time with novel mice (P=0.014 and P=0.028, respectively; N=11). Modulating distinct serotonin receptors (5‐HTRs) can regulate MMP‐9 expression, neuroanatomical plasticity, social behaviors, and memory. Previously we showed that FPT, a novel medication candidate with potent 5‐HT1AR agonist activity, increases social interactions in adult Fmr1KO and WT mice (Armstrong et al., 2020 https://doi.org/10.1021/acsptsci.9b00101). However, we did not investigate FPT’s effects on social behavior or social memory in juvenile mice—focusing on critical neurodevelopmental periods—nor have we explored mechanisms underlying FPT’s therapeutic‐like effects. We are now testing the hypothesis that FPT corrects social memory deficits in juvenile Fmr1 KO mice and works, in part, by decreasing MMP‐9 levels and restoring PNN levels in hippocampal CA2 via a 5‐HT1AR mechanism. Results from these studies will provide critical mechanistic information regarding the preclinical neurotherapeutic effects of FPT in FXS.