Long Term High-Salt Diet Induces Cognitive Impairments via Down-Regulating SHANK1.

ABSTRACT: High-salt (HS) diet is an established risk factor for cognitive impairment, but the underlying mechanisms remain unclear. This study reveals that HS diet reduces SHANK1, a key postsynaptic scaffolding protein, via downregulation of the PKA/CREB pathway, leading to synaptic dysfunction and cognitive deficits in rats. RNA sequencing of HS-fed rat hippocampi showed downregulation of cAMP signaling and SHANK1 expression. Pharmacological inhibition of PKA/CREB reduced SHANK1 levels and impaired dendritic structure and synaptic function, while PKA activation restored CREB activity and SHANK1 expression, reversing HS-induced deficits. Notably, CREB activation is essential for SHANK1 regulation, as a CREB mutant (S133A) blocked the effects of PKA activation, and a constitutively active CREB (S133D

SUBMITTER: Guo C 

PROVIDER: S-EPMC12463032 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature