title: Behavioral characterization of cereblon forebrain-specific conditional null mice: a model for human non-syndromic intellectual disability.
abstract: A nonsense mutation in the human cereblon gene (CRBN) causes a mild type of autosomal recessive non-syndromic intellectual disability (ID). Animal studies show that crbn is a cytosolic protein with abundant expression in the hippocampus (HPC) and neocortex (CTX). Its diverse functions include the developmental regulation of ion channels at the neuronal synapse, the mediation of developmental programs by ubiquitination, and a target for herpes simplex type I virus in HPC neurons. To test the hypothesis that anomalous CRBN expression leads to HPC-mediated memory and learning deficits, we generated germ-line crbn knock-out mice (crbn(-/-)). We also inactivated crbn in forebrain neurons in conditional knock-out mice in which crbn exons 3 and 4 are deleted by cre recombinase under the direction of the Ca(2+)/calmodulin-dependent protein kinase II alpha promoter (CamKII(cre/+), crbn(-/-)). crbn mRNA levels were negligible in the HPC, CTX, and cerebellum (CRBM) of the crbn(-/-) mice. In contrast, crbn mRNA levels were reduced 3- to 4-fold in the HPC, CTX but not in the CRBM in CamKII(cre/+), crbn(-/-) mice as compared to wild type (CamKII(cre/+), crbn(+/+)). Contextual fear conditioning showed a significant decrease in the percentage of freezing time in CamKII(cre/+), crbn(-/-) and crbn(-/-) mice while motor function, exploratory motivation, and anxiety-related behaviors were normal. These findings suggest that CamKII(cre/+), crbn(-/-) mice exhibit selective HPC-dependent deficits in associative learning and supports the use of these mice as in vivo models to study the functional consequences of CRBN aberrations on memory and learning in humans.
authors: Department of Pediatrics, Division of Pediatric Neurology, New York Presbyterian Hospital, Laboratory of Molecular and Developmental Neurobiology, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
authors: Anjali M
authors: AM
authors: Rajadhyaksha
authors: Stephen
authors: S
authors: Ra
authors: Sarah
authors: S
authors: Kishinevsky
authors: Anni S
authors: AS
authors: Lee
authors: Peter
authors: P
authors: Romanienko
authors: Mariel
authors: M
authors: DuBoff
authors: Chingwen
authors: C
authors: Yang
authors: Bojana
authors: B
authors: Zupan
authors: Maureen
authors: M
authors: Byrne
authors: Zeeba R
authors: ZR
authors: Daruwalla
authors: Willie
authors: W
authors: Mark
authors: Barry E
authors: BE
authors: Kosofsky
authors: Miklos
authors: M
authors: Toth
authors: Joseph J
authors: JJ
authors: Higgins
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001483:Base Sequence / Q000235:genetics / Q000502:physiology; D003214:Conditioning, Classical / Q000502:physiology; D004195:Disease Models, Animal; D005091:Exons / Q000235:genetics; D005239:Fear / Q000502:physiology; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology*; D016548:Prosencephalon / Q000502:physiology*; D017384:Sequence Deletion / Q000235:genetics / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C549921:Crbn protein, mouse; D009419:Nerve Tissue Proteins