Synaptic plasticity deficits in a mouse model of Timothy syndrome: LTP saturation and its pharmacological rescue by nifedipine.

Timothy syndrome (TS) is a multisystem disorder characterized by cardiovascular abnormalities and a spectrum of neuropsychiatric symptoms, including language impairment, seizure, cognitive disability and autism. TS is caused by gain of function mutations in the CACNA1C gene that encodes the CaV1.2 L-type calcium channel. TS mutations have been reported to disrupt hippocampal long-term potentiation (LTP), a process implicated in memory formation. Here, we compared wild type (WT) and heterozygous G406R CaV1.2 mutant TS2-neo model mice using a LTP saturation protocol consisting of two successive theta burst stimuli. While WT mice showed potentiated synaptic strength in response to both theta-burst stimuli, TS2-neo mutants exhibited a smaller initial LTP and minimal responses to the second stimulus. The dihydropyridine L-type calcium channel blocker, nifedipine, inhibited LTP in WT mice, but enhanced both the initial and the second LTP in TS2-neo mutants. By measuring the phosphorylation activation of ERK, CREB and glutamate receptor GluR1, steps required for hip- pocampal LTP, we found that all were abnormally high at baseline in the mutant mice. Nifedipine blocked LTP- related phosphorylation in WT mice, but normalized baseline phosphorylation of ERK, CREB and GluR1 in TS2- neo mice, allowing their subsequent activity-dependent induction. Thus, while nifedipine inhibits LTP in WT mice, the drug reinstates LTP and normal synaptic plasticity in a TS model, suggesting potential therapeutic approaches for synaptic deficits in channelopathies such as TS.