Journal
BEHAVIOURAL BRAIN RESEARCH
Volume 226, Issue 2, Pages 428-434Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbr.2011.09.039
Keywords
Non-syndromic mental retardation; Cereblon; Conditional knock-out mice; Fear conditioning; Memory; Association learning
Categories
Funding
- March of Dimes Birth Defects Foundation [12-FY08-152]
- Hartwell Foundation
- Weill Cornell Medical College Clinical Translational Science Center [UL1-RR024996]
Ask authors/readers for more resources
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 11 alpha promoter (CamKIIcre/(+), 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 CamKIIcre/(+), crbn(-/-) mice as compared to wild type (CamKII(cre/+), crbn(+/+).). Contextual fear conditioning showed a significant decrease in the percentage of freezing time in CamKlIcre/(+), crbn(-/-) and crbn(-/-) mice while motor function, exploratory motivation, and anxiety-related behaviors were normal. These findings suggest that CamKII(cre/+), crbn-1- 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. (C) 2011 Elsevier B.V. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available