Kalirin regulates cortical spine morphogenesis and disease-related behavioral phenotypes

Michael E. Cahill; Zhong Xie; Michelle Day; Maria V. Barbolina; Courtney A. Miller; Craig Weiss; Jelena Radulovic; J. David Sweatt; John F. Disterhoft; D. James Surmeier; Peter Penzes

doi:10.1073/pnas.0904636106

Kalirin regulates cortical spine morphogenesis and disease-related behavioral phenotypes

Michael E. Cahill, Zhong Xie, Michelle Day, Maria V. Barbolina, Courtney A. Miller, Craig Weiss, Jelena Radulovic, J. David Sweatt, John F. Disterhoft, D. James Surmeier, Peter Penzes

Research output: Contribution to journal › Article › peer-review

136 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	13058-13063
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	106
Issue number	31
DOIs	https://doi.org/10.1073/pnas.0904636106
State	Published - Aug 4 2009
Externally published	Yes

Keywords

Alzheimer's disease
Antipsychotic
Prefrontal cortex
Schizophrenia
Synaptic plasticity

ASJC Scopus subject areas

General

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10.1073/pnas.0904636106

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Cahill, M. E., Xie, Z., Day, M., Barbolina, M. V., Miller, C. A., Weiss, C., Radulovic, J., Sweatt, J. D., Disterhoft, J. F., Surmeier, D. J., & Penzes, P. (2009). Kalirin regulates cortical spine morphogenesis and disease-related behavioral phenotypes. Proceedings of the National Academy of Sciences of the United States of America, 106(31), 13058-13063. https://doi.org/10.1073/pnas.0904636106

Cahill, ME, Xie, Z, Day, M, Barbolina, MV, Miller, CA, Weiss, C, Radulovic, J, Sweatt, JD, Disterhoft, JF, Surmeier, DJ & Penzes, P 2009, 'Kalirin regulates cortical spine morphogenesis and disease-related behavioral phenotypes', Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 31, pp. 13058-13063. https://doi.org/10.1073/pnas.0904636106

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abstract = "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.",

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AU - Cahill, Michael E.

AU - Xie, Zhong

AU - Day, Michelle

AU - Barbolina, Maria V.

AU - Miller, Courtney A.

AU - Weiss, Craig

AU - Radulovic, Jelena

AU - Sweatt, J. David

AU - Disterhoft, John F.

AU - Surmeier, D. James

AU - Penzes, Peter

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AB - 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.

KW - Alzheimer's disease

KW - Antipsychotic

KW - Prefrontal cortex

KW - Schizophrenia

KW - Synaptic plasticity

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Kalirin regulates cortical spine morphogenesis and disease-related behavioral phenotypes

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