title: Kalirin regulates cortical spine morphogenesis and disease-related behavioral phenotypes.
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.
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cahill
authors.forename: Zhong
authors.initials: Z
authors.lastname: Xie
authors.forename: Michelle
authors.initials: M
authors.lastname: Day
authors.forename: Huzefa
authors.initials: H
authors.lastname: Photowala
authors.forename: Maria V
authors.initials: MV
authors.lastname: Barbolina
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Miller
authors.forename: Craig
authors.initials: C
authors.lastname: Weiss
authors.forename: Jelena
authors.initials: J
authors.lastname: Radulovic
authors.forename: J David
authors.initials: JD
authors.lastname: Sweatt
authors.forename: John F
authors.initials: JF
authors.lastname: Disterhoft
authors.forename: D James
authors.initials: DJ
authors.lastname: Surmeier
authors.forename: Peter
authors.initials: P
authors.lastname: Penzes
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002478:Cells, Cultured; D003024:Clozapine / Q000494:pharmacology; D003071:Cognition; D049229:Dendritic Spines / Q000502:physiology*; D005625:Frontal Lobe / Q000166:cytology*; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D008297:Male; D018782:Maze Learning; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis; D009043:Motor Activity; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission; D020764:cdc42 GTP-Binding Protein / Q000502:physiology
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C102365:Kalrn protein, rat; D020764:cdc42 GTP-Binding Protein; D003024:Clozapine