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journal article·2025-09Open access

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

Cuiping Guo, Yuanyuan Li, Wensheng Li, Tongrui Wu, Yi Liu, Yacoubou Abdoul Razak Mahaman, Jianzhi Wang, Rong Liu, Wei Liu, Hui Shen, Xiaochuan Wang

Advanced Science· Volume 12· Issue 36
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Source abstract

Abstract

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) prevented SHANK1 downregulation. These findings highlight the PKA/CREB/SHANK1 pathway as a potential therapeutic target for HS‐induced cognitive dysfunction.
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Research context

OpenAlex topics: Neuroscience and Neuropharmacology Research · Ion Transport and Channel Regulation · Sodium Intake and Health

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Institutes of Biomedical Sciences School of Medicine Hubei Key Laboratory of Cognitive and Affective Disorders Jianghan University Wuhan 430056 China

Department of Pathophysiology School of Basic Medicine Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China

Department of Emergency Medicine & Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China

Laboratory of Neurobiology School of Basic medicine Tianjin Medical University Tianjin 300070 China

Hubei Provincial Key Laboratory of Kidney Diseases Occurrence and Intervention School of Medicine Hubei Polytechnic University Huangshi Hubei Province 435003 China

Co‐innovation Center of Neuroregeneration Nantong University Nantong 226001 China

Department of Ophthalmology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan 430022 China

Funding

National Natural Science Foundation of China · Department of Science and Technology of Hubei Province

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