Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 31, Pages 13058-13063Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0904636106
Keywords
prefrontal cortex; antipsychotic; schizophrenia; Alzheimer's disease; synaptic plasticity
Categories
Funding
- National Institutes of Health-National Institute of Mental Health [R01MH071316, MH57014, P01 MH074866]
- National Alliance for Autism Research
- National Alliance for Research on Schizophrenia and Depression
- Evelyn F. McKnight
- National Institute on Aging [R37 AG08796, F31AG031621-01A2]
- National Institutes of Health-National Institute of Neurological Disorders and Stroke [R37 NS034696]
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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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