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

UNLABELLED

Fragile X syndrome (FXS), the most common monogenic neurodevelopmental disorder associated with autism and intellectual disability, results from the loss of expression of the gene. Synaptic and circuit-level abnormalities are well documented in FXS and extensively studied in the 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 KO mice. Here we examined whether state-dependent synaptic plasticity in CA1, in which prior "priming" activity modulates subsequent synaptic plasticity, was affected in KO mice. We found that NMDA receptor activation prior to LTP induction produced metaplastic inhibition of LTP, which was exaggerated in 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 KO slices, implicating altered SK activity in the exaggerated LTP inhibition in KO mice. These finding reveal a disrupted coupling between NMDA receptors and SK channels in 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 KO mice.

SIGNIFICANCE STATEMENT

While conventional synaptic plasticity (LTP and LTD) has been extensively examined in 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 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.