Exaggerated NMDA Receptor-Primed Metaplasticity via SK Channel Dysregulation in <i>Fmr1</i> Knockout Mice

Abstract

Fragile X syndrome (FXS), the most common monogenic neurodevelopmental disorder associated with autism and intellectual disability, results from the loss of expression of the X-linked FMR1 gene. Synaptic and circuit-level abnormalities in the brain are well documented in FXS and extensively studied in the Fmr1 KO mouse model. In CA1 hippocampal neurons, functional, molecular, and structural synaptic changes have been described, yet the canonical form of Hebbian CA1 long-term potentiation (LTP) remains intact in Fmr1 KO mice. Here we examined whether state-dependent synaptic plasticity in CA1, in which prior “priming” activity modulates subsequent synaptic plasticity, was altered in male Fmr1 KO mice. We found that NMDA receptor activation prior to LTP induction produced metaplastic inhibition of LTP, which was exaggerated in Fmr1 KO mice. This effect was mediated by the activity of small conductance calcium-activated potassium (SK) channels which was enhanced after NMDA priming and dampened dendritic excitability. Blocking SK channels during NMDA-primed LTP induction eliminated the abnormal metaplasticity in Fmr1 KO slices, implicating altered SK activity in the exaggerated LTP inhibition in Fmr1 KO mice. These finding reveal a disrupted functional coupling between NMDA receptors and SK channels in Fmr1 KO mice, altering the impact of priming on LTP expression in the CA1. Altered metaplasticity may represent a neural correlate of impaired hippocampal function in Fmr1 KO mice and potentially contribute to clinical manifestations in FXS individuals.