Scn1a ‐mediated developmental regulation of prefrontal cortex plasticity and cognition

Abstract Objective The voltage‐gated sodium channel Nav1.1, encoded by Scn1a , is essential for γ‐aminobutyric acid (GABA)ergic function, and its alteration is associated with neurological disorders such as Dravet syndrome and Alzheimer's disease. We previously demonstrated that local Nav1.1 dysfunction in the medial prefrontal cortex (mPFC) during adolescence causes epilepsy, cognitive deficits, and depressive‐like behaviors. Here, to investigate putative developmental differences, we analyzed whether Nav1.1 dysfunction in the adult mPFC produces comparable phenotypic outcomes. Methods Nav1.1 dysfunction was selectively induced in the adult mPFC via conditional expression of a mutant human SCN1A variant. We then analyzed PFC‐related cognitive tasks and depressive‐like behaviors; epileptic and oscillatory activity using in vivo electroencephalography (EEG) recordings; and ex vivo synaptic plasticity in mPFC circuits. Results As observed after adolescent Nav1.1 dysfunction, adult manipulation induced epileptic activity and depressive‐like phenotypes. However, mPFC‐dependent cognitive functions remained intact, unlike adolescent mice, which showed impaired working memory and fear extinction. Electrophysiological recordings revealed distinct mPFC oscillatory patterns. Adult Nav1.1 dysfunction reduced sleep‐related delta mPFC power and dorsal hippocampus (dHPC)–mPFC coherence, mimicking adolescent patterns. In contrast, no alteration in mPFC oscillatory activity was observed during wakefulness, differing from adolescent mice. IN addition, synaptic plasticity analyses showed that adolescent—but not adult—Nav1.1 dysfunction impaired long‐term potentiation (LTP) at cortical L2/3–L2/3 prelimbic synapses. Moreover, LTP was sensitive to Nav1.1 pharmacological activation only in adolescent mice. Significance These findings reveal a developmental role for Nav1.1 activity in mPFC plasticity and cognition, whereas in adulthood, it remains critical for regulating network stability and depressive‐like behaviors.