Evidence map›Paper›PMID 40016780›Full record

ArticleAlzheimer's research & therapy2025

HCN2 deficiency correlates with memory deficits and hyperexcitability of dCA1 pyramidal neurons in Alzheimer's disease.

Xiaoqin Zhang, Yiping Zhang, Ting Zhang, Jing Wang, Chang Liu, Qing Shang, Xiaojie Wei, Huaqiang Zhu, Haowei Shen, Binggui Sun

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Alzheimer's research & therapy, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

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Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

6 citing papers in PubMed.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors.

Xiaoqin Zhang *Department of Pharmacology, Health Science Center of Ningbo University, Ningbo, Zhejiang Province, 315211, China. zhangxiaoqin1@nbu.edu.cn.
Yiping Zhang *Department of Anesthesiology of the Children's Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine and National Clinical Research Center for Child Health; NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310058, China.
Ting ZhangDepartment of Pharmacology, Health Science Center of Ningbo University, Ningbo, Zhejiang Province, 315211, China.
Jing WangDepartment of Anesthesiology of the Children's Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine and National Clinical Research Center for Child Health; NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310058, China.
Chang LiuDepartment of Pharmacology, Health Science Center of Ningbo University, Ningbo, Zhejiang Province, 315211, China.
Qing ShangDepartment of Neurology, The First Affiliated Hospital of Ningbo University, 59 Liuting Street, Haishu District, Ningbo, Zhejiang Province, 315211, China.
Xiaojie WeiDepartment of Anesthesiology of the Children's Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine and National Clinical Research Center for Child Health; NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310058, China.
Huaqiang ZhuZhejiang Pharmaceutical College, Ningbo, Zhejiang Province, 315100, China.
Haowei ShenDepartment of Pharmacology, Health Science Center of Ningbo University, Ningbo, Zhejiang Province, 315211, China. shenhaowei@nbu.edu.cn.
Binggui SunDepartment of Anesthesiology of the Children's Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine and National Clinical Research Center for Child Health; NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310058, China. bsun@zju.edu.cn.

Funding

National Key Research and Development Program of China 2021YFA1101701National Natural Science Foundation of China 32201322National Natural Science Foundation of China 32271028Natural Science Foundation of Zhejiang Province LY24H090001
6 · The paper itself

Abstract

backgroundAbnormal excitability of hippocampal neurons may lead to dysfunction of neural circuits and then causes cognitive impairments in Alzheimer's disease (AD). However, the underlying mechanisms remain to be fully elucidated.

methodsElectrophysiology was performed to examine the intrinsic excitability of CA1 neurons and the activity of the hyperpolarization-activated cyclic nucleotide-gated ion channels (HCNs) of CA1 neurons in wild type (WT) and hAPP-J20 mice. The activity of CA1 pyramidal neurons (PNs) was modulated with chemogenetics. The activity of HCNs was regulated with nonselective facilitator (cAMP) or inhibitor (ZD7288) of HCNs. Immunohistochemical staining or western blotting were performed to examine the expression of HCN1 and HCN2 in the hippocampus of WT and hAPP-J20 mice, or AD patients and non-AD controls. AAVs were injected to specifically modulate the expression of HCN2 in dorsal CA1 (dCA1) PNs. Cognitive performance of mice was assessed with behavioral tests.

resultsdCA1 PNs were more excitable in hAPP-J20 mice, but the excitability of PNs in the ventral CA1 (vCA1) or PV neurons was comparable between WT and hAPP-J20 mice. The activity of the HCNs was reduced in dCA1 PNs of hAPP-J20 mice, and pharmacologically increasing the activity of HCNs attenuated the hyperexcitability of dCA1 PNs in hAPP-J20 mice, suggesting that the reduced activity of HCNs is associated with the hyperexcitability of dCA1 PNs in hAPP-J20 mice. The expression of HCN2 but not HCN1 was reduced in the hippocampus of hAPP-J20 mice, and the expression of HCN2 was also reduced in the hippocampus of AD patients, suggesting that dysregulation of HCN2 is associated with the reduced activity of HCNs in AD. Overexpressing HCN2 rescued the activity of HCNs, attenuated the hyperexcitability of dCA1 PNs and improved memory of hAPP-J20 mice, and knocking down HCN2 impaired the function of HCNs, increased the excitability of dCA1 PNs and led to memory deficits in WT mice.

conclusionsOur data suggest that dysregulation of HCNs, particularly HCN2, contributes to the abnormal excitability of CA1 PNs in AD mice and probably in AD patients as well, and thus provide new insights into the mechanisms underlying the aberrant activity or excitability of hippocampal neurons in AD.

Indexed as

Alzheimer DiseaseCA1 Region, HippocampalHyperpolarization-Activated Cyclic Nucleotide-Gated ChannelsMemory DisordersPotassium ChannelsPyramidal CellsAgedAnimalsDisease Models, AnimalFemaleHumansMaleMiceMice, Inbred C57BLMice, TransgenicHCN2 protein, humanHcn2 protein, mouseHyperpolarization-Activated Cyclic Nucleotide-Gated ChannelsPotassium ChannelsAlzheimer’s diseaseAβCA1 pyramidal neuronsHCN2Hyperexcitability

Identifiers

PMID40016780
PMCPMC11866685

What Socratic holds

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.