Kalirin regulates cortical spine morphogenesis and disease-related behavioral phenotypes

被引：139

作者：

Cahill, Michael E. ^{[1
]}

Xie, Zhong ^{[1
]}

Day, Michelle ^{[1
]}

Barbolina, Maria V. ^{[4
]}

Miller, Courtney A. ^{[5
,6
]}

Weiss, Craig ^{[1
]}

Radulovic, Jelena ^{[2
,3
]}

Sweatt, J. David ^{[5
,6
]}

Disterhoft, John F. ^{[1
]}

Surmeier, D. James ^{[1
]}

Penzes, Peter ^{[1
]}

机构：

[1] Northwestern Univ, Feinberg Sch Med, Dept Physiol, Chicago, IL 60611 USA

[2] Northwestern Univ, Feinberg Sch Med, Dept Psychiat & Behav Sci, Chicago, IL 60611 USA

[3] Northwestern Univ, Feinberg Sch Med, Asher Ctr Depress Disorders, Chicago, IL 60611 USA

[4] Univ Illinois, Dept Biopharmaceut Sci, Chicago, IL 60612 USA

[5] Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA

[6] Univ Alabama, Evelyn F McKnight Brain Inst, Birmingham, AL 35294 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2009年 / 106卷 / 31期

基金：

美国国家卫生研究院;

关键词：

prefrontal cortex; antipsychotic; schizophrenia; Alzheimer's disease; synaptic plasticity; GDP/GTP EXCHANGE FACTOR; WORKING-MEMORY; ALZHEIMERS-DISEASE; PREPULSE INHIBITION; DENDRITIC STRUCTURE; EXECUTIVE FUNCTIONS; MENTAL-RETARDATION; PREFRONTAL CORTEX; SOCIAL-BEHAVIOR; MICE LACKING;

D O I：

10.1073/pnas.0904636106

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Dendritic spine morphogenesis contributes to brain function, cognition, and behavior, and is altered in psychiatric disorders. Kalirin is a brain-specific guanine-nucleotide exchange factor (GEF) for Rac-like GTPases and is a key regulator of spine morphogenesis. Here, we show that KALRN-knockout mice have specific reductions in cortical, but not hippocampal, Rac1 signaling and spine density, and exhibit reduced cortical glutamatergic transmission. These mice exhibit robust deficits in working memory, sociability, and prepulse inhibition, paralleled by locomotor hyperactivity reversible by clozapine in a kalirin-dependent manner. Several of these deficits are delayed and age-dependent. Our study thus links spine morphogenic signaling with age-dependent, delayed, disease-related phenotypes, including cognitive dysfunction.

引用

页码：13058 / 13063

页数：6

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