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Sanderson, Jennifer L.; Freund, Ronald K.; Castano, Anna M.; Benke, Timothy A.; Dell’Acqua, Mark L.
Neuropharmacology, 12/2022, Letnik: 220Journal Article
Genetic alterations in autism spectrum disorders (ASD) frequently disrupt balance between synaptic excitation and inhibition and alter plasticity in the hippocampal CA1 region. Individuals with Timothy Syndrome (TS), a genetic disorder caused by CaV1.2 L-type Ca2+ channel (LTCC) gain-of function mutations, such as G406R, exhibit social deficits, repetitive behaviors, and cognitive impairments characteristic of ASD that are phenocopied in TS2-neo mice expressing G406R. Here, we characterized hippocampal CA1 synaptic function in male TS2-neo mice and found basal excitatory transmission was slightly increased and inhibitory transmission strongly decreased. We also found distinct impacts on two LTCC-dependent forms of long-term potentiation (LTP) synaptic plasticity that were not readily consistent with LTCC gain-of-function. LTP induced by high-frequency stimulation (HFS) was strongly impaired in TS2-neo mice, suggesting decreased LTCC function. Yet, CaV1.2 expression, basal phosphorylation, and current density were similar for WT and TS2-neo. However, this HFS-LTP also required GABAA receptor activity, and thus may be impaired in TS2-neo due to decreased inhibitory transmission. In contrast, LTP induced in WT mice by prolonged theta-train (PTT) stimulation in the presence of a β-adrenergic receptor agonist to increase CaV1.2 phosphorylation was partially induced in TS2-neo mice by PTT stimulation alone, consistent with increased LTCC function. Overall, our findings provide insights regarding how altered CaV1.2 channel function disrupts basal transmission and plasticity that could be relevant for neurobehavioral alterations in ASD. This article is part of the Special Issue on ‘L-type calcium channel mechanisms in neuropsychiatric disorders’. Display omitted •CaV1.2 G406R mutation in Timothy Syndrome decreases CA1 synaptic inhibition.•G406R inhibits L-type Ca2+ channel dependent, high-frequency stimulation/HFS-LTP.•G406R sensitizes synapses to potentiation by prolonged theta train/PTT stimulation.•G406R partially occludes β-adrenergic promotion of CaV1.2-dependent PTT-LTP.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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