Kalirin regulates cortical spine morphogenesis and disease-related behavioral phenotypes.
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.
Cahill
Michael E
ME
Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Xie
Zhong
Z
Day
Michelle
M
Photowala
Huzefa
H
Barbolina
Maria V
MV
Miller
Courtney A
CA
Weiss
Craig
C
Radulovic
Jelena
J
Sweatt
J David
JD
Disterhoft
John F
JF
Surmeier
D James
DJ
Penzes
Peter
P
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
D020662:Guanine Nucleotide Exchange Factors; C102365:Kalrn protein, rat; D020764:cdc42 GTP-Binding Protein; D003024:Clozapine