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

doi:10.1002/advs.202502099

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

Adv Sci (Weinh). 2025 Jun 26:e02099. doi: 10.1002/advs.202502099. Online ahead of print.

Authors

Cuiping Guo^{1

2

3}, Yuanyuan Li⁴, Wensheng Li², Tongrui Wu⁴, Yi Liu², Yacoubou Abdoul Razak Mahaman^{2

5}, Jianzhi Wang^{1

2

6}, Rong Liu², Wei Liu⁷, Hui Shen⁴, Xiaochuan Wang^{1

2

3

6}

Affiliations

¹ Institutes of Biomedical Sciences, School of Medicine, Hubei Key Laboratory of Cognitive and Affective Disorders, Jianghan University, Wuhan, 430056, China.
² 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.
³ Department of Emergency Medicine & Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
⁴ Laboratory of Neurobiology, School of Basic medicine, Tianjin Medical University, Tianjin, 300070, China.
⁵ Hubei Provincial Key Laboratory of Kidney Diseases Occurrence and Intervention, School of Medicine, Hubei Polytechnic University, Huangshi, Hubei Province, 435003, China.
⁶ Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China.
⁷ Department of Ophthalmology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

PMID: 40574425
DOI: 10.1002/advs.202502099

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.

Keywords: PKA/CREB; SHANK1; cognitive deficits; high‐salt diet; synaptic dysfunction.

Abstract

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