Hyper-excitability of corticothalamic PT neurons in mPFC promotes irritability in the mouse model of Alzheimer's disease

Zhongyu Zhang; Ying Zhang; Ting Yuwen; Jiaxin Huo; Enyu Zheng; Wen Zhang; Jiali Li

doi:10.1016/j.celrep.2022.111577

Hyper-excitability of corticothalamic PT neurons in mPFC promotes irritability in the mouse model of Alzheimer's disease

Cell Rep. 2022 Nov 1;41(5):111577. doi: 10.1016/j.celrep.2022.111577.

Authors

Zhongyu Zhang¹, Ying Zhang², Ting Yuwen³, Jiaxin Huo³, Enyu Zheng³, Wen Zhang⁴, Jiali Li⁵

Affiliations

¹ National Institute on Drug Dependence, Peking University, Beijing, China; Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; PKU/McGovern Institute for Brain Research, Peking University, Beijing, China.
² Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, the Chinese Academy of Sciences, Kunming, Yunnan, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China.
³ National Institute on Drug Dependence, Peking University, Beijing, China; PKU/McGovern Institute for Brain Research, Peking University, Beijing, China.
⁴ National Institute on Drug Dependence, Peking University, Beijing, China.
⁵ National Institute on Drug Dependence, Peking University, Beijing, China; Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, the Chinese Academy of Sciences, Kunming, Yunnan, China; PKU/McGovern Institute for Brain Research, Peking University, Beijing, China; National Resource Center for Non-Human Primates, Kunming Primate Research Center, National Research Facility for Phenotypic and Genetic Analysis of Model Animals (Primate Facility), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China. Electronic address: jialili@bjmu.edu.cn.

PMID: 36323265
DOI: 10.1016/j.celrep.2022.111577

Abstract

Neuropsychiatric symptoms in patients with Alzheimer's disease (AD) are presented as early as the mild cognitive impairment (MCI) stage. However, it remains unclear whether separate neuronal populations encode distinct aspects of the neuropsychiatric symptoms and drive them differently. Here, we report that pyramidal tract (PT) neurons projecting to the thalamus, but not to the pons or medulla, in the medial prefrontal cortex (mPFC) of the mouse model of AD show increased excitability, which is associated with increased irritability and aggressivity. Decreased Kv6.3 in corticothalamic PT neurons contributes to hyper-excitability, which is tightly associated with aggressive behaviors. Overexpression of Kv6.3 not only prevents abnormal excitability of corticothalamic PT neurons in mPFC, but also rescues aggressive behaviors of 3xTg model mice. Our study provides causal evidence for the contribution of corticothalamic PT neurons to irritability in the 3xTg model of AD and reveals circuit mechanisms used by PT neurons to regulate neuropsychiatric symptoms in AD.

Keywords: Alzheimer’s disease; CP: Neuroscience; Kv6.3 channel; aggressive behavior; medial prefrontal cortex; pyramidal tract neurons.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease*
Animals
Disease Models, Animal
Mice
Neurons / physiology
Prefrontal Cortex / physiology
Pyramidal Cells / physiology
Pyramidal Tracts