Selectively enhanced contextual fear conditioning in mice lacking the transcriptional regulator CCAAT/enhancer binding protein δ

Selectively enhanced contextual fear conditioning in mice lacking the transcriptional regulator CCAAT/enhancer binding protein δ

^*Eukaryotic Transcriptional Regulation Section and ^‖Neural Development Group, Advanced BioScience Laboratories-Basic Research Program, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702; ^¶Neuroscience Research, Movement Disorders Division, Department of Neurology, Columbia University, New York, NY 10032; and ^‡Section on Behavioral Neuropharmacology, Experimental Therapeutics Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892

Communicated by William T. Greenough, University of Illinois, Urbana, IL (received for review December 3, 1997)

Abstract

CCAAT/enhancer binding protein δ (C/EBPδ) is a transcriptional regulator implicated in the hepatic acute phase response and in adipogenic and myeloid cell differentiation. We found that C/EBPδ is widely expressed in the peripheral and central nervous systems, including neurons of the hippocampal formation, indicating a role in neural functions. To examine the role of C/EBPδ in vivo, we generated mice with a targeted deletion of the C/EBPδ gene. This mutation does not interfere with normal embryonic and postnatal development. Performance in a battery of behavioral tests indicates that basic neurological functions are normal. Furthermore, performance in a Morris water maze task suggests that C/EBPδ mutant mice have normal spatial learning. However, in the contextual and auditory-cue-conditioned fear task, C/EBPδ null mice displayed significantly more conditioned freezing to the test context than did wild-type controls, but equivalent conditioning to the auditory cue. These data demonstrate a selectively enhanced contextual fear response in mice carrying a targeted genomic mutation and implicate C/EBPδ in the regulation of a specific type of learning and memory.

Footnotes

↵ † E.S. and R.P. contributed equally to this work.
↵ § Present address: Department of Molecular and Human Genetics, and Division of Neuroscience, Baylor College of Medicine, Houston, TX 77030.
↵ ** To whom reprint requests should be addressed. e-mail: johnsopf{at}ncifcrf.gov.
ABBREVIATIONS:

C/EBP,

CCAAT/enhancer binding protein;

CREB,

cAMP response element binding protein;

ES,

embryonic stem;

wt,

wild type;

CS,

conditioned stimulus;

Exp.,

experiment;

M,

male;

F,

female