Exaggerated NMDA Receptor-Primed Metaplasticity via SK Channel Dysregulation in Fmr1 Knockout Mice

Fragile X syndrome (FXS), the most common monogenic neurodevelopmental disorder associated with autism and intellectual disability, results from the loss of expression of the FMR1 gene. Synaptic and circuit-level abnormalities 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 affected in 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 coupling between NMDA receptors and SK channels in Fmr1 KO mice, which alters the impact of priming on LTP expression in the CA1. Altered metaplasticity may represent a neural correlate of impaired adaptive hippocampal learning in Fmr1 KO mice.

While conventional synaptic plasticity (LTP and LTD) has been extensively examined in Fmr1 KO mice, evidence about the integrity of metaplasticity in these mice has been limited. This study provides a characterization of alterations in NMDA receptor mediated metaplasticity in the hippocampus in Fmr1 KO mice. The question of whether hippocampal LTP is altered in these mice remains unresolved, and changes in metaplasticity may partly explain the discrepancies across studies. Our findings not only identify novel synaptic phenotypes and their underlying mechanisms in the FXS mouse model, but also highlight potential therapeutic targets for FXS.