title: Mice null for NEDD9 (HEF1α) display extensive hippocampal dendritic spine loss and cognitive impairment.
abstract: NEDD9 (neural precursor cell expressed, developmentally down-regulated 9) is a member of the CAS (Crk-associated substrate) family of scaffolding proteins that regulate cell adhesion and migration. A Nedd9 knock-out/lacZ knock-in mouse (Nedd9(-/)(-)) was developed in order to study Nedd9 expression and function in the nervous system. Herein we show that NEDD9 is expressed in the adult brain and is prominently expressed in the hippocampus. Behavioral testing uncovered functional deficits in Nedd9(-)(/)(-) mice. In the Morris water maze test, Nedd9(-)(/)(-) mice showed deficits in both the ability to learn the task as well as in their ability to recall the platform location. There was no change in the gross morphology of the hippocampus, and stereological analysis of BrdU-labeled newly formed hippocampal cells suggested that this defect is not secondary to altered neurogenesis. However, analysis of the hippocampus revealed extensive loss of dendritic spine density in both the dentate gyrus (DG) and CA1 regions. Spine loss occurred equally across all branch orders and regions of the dendrite. Analysis of spine density in Nedd9(-)(/)(-) mice at 1.5, 6 and 10 months revealed an age-dependent spine loss. This work shows that NEDD9 is required for the maintenance of dendritic spines in the hippocampus, and suggests it could play a role in learning and memory.
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Knutson
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Mitzey
authors.affiliation: Behavioral Testing Core Facility, University of California, Los Angeles, CA 90095, USA.
authors.forename: L E
authors.initials: LE
authors.lastname: Talton
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA; Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705, USA. Electronic address: dame@biochem.wisc.edu.
authors.forename: M
authors.initials: M
authors.lastname: Clagett-Dame
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency*; D000818:Animals; D003072:Cognition Disorders / Q000378:metabolism* / Q000473:pathology; D049229:Dendritic Spines / Q000378:metabolism* / Q000473:pathology; D005260:Female; D055879:Gene Knock-In Techniques; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C505592:NEDD9 protein, mouse
keywords: CAS; Dendritic spine density; Hippocampus; NEDD9; Null mutant; Retinoic acid-induced differentiation