TitleBehavioral characterization of cereblon forebrain-specific conditional null mice: a model for human non-syndromic intellectual disability.
Publication TypeJournal Article
Year of Publication2012
AuthorsRajadhyaksha AM, Ra S, Kishinevsky S, Lee AS, Romanienko P, DuBoff M, Yang C, Zupan B, Byrne M, Daruwalla ZR, Mark W, Kosofsky BE, Toth M, Higgins JJ
JournalBehav Brain Res
Date Published2012 Jan 15
KeywordsAnimals, Base Sequence, Conditioning, Classical, Disease Models, Animal, Exons, Fear, Humans, Intellectual Disability, Male, Maze Learning, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Motor Activity, Nerve Tissue Proteins, Prosencephalon, Sequence Deletion

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.

Alternate JournalBehav. Brain Res.
PubMed ID21995942
Grant ListR01 MH058669 / MH / NIMH NIH HHS / United States
UL1-RR024996 / RR / NCRR NIH HHS / United States