CCAAT͞enhancer binding protein ␦ (C͞ EBP␦) is a transcriptional regulator implicated in the hepatic acute phase response and in adipogenic and myeloid cell differentiation. We found that C͞EBP␦ 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 C͞EBP␦ in vivo, we generated mice with a targeted deletion of the C͞EBP␦ 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 C͞EBP␦ mutant mice have normal spatial learning. However, in the contextual and auditory-cueconditioned fear task, C͞EBP␦ 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 C͞EBP␦ in the regulation of a specific type of learning and memory.The CCAAT͞enhancer binding protein (C͞EBP) family of transcriptional regulators is composed of five related basicleucine zipper DNA-binding proteins (C͞EBP␣, C͞EBP␤, C͞EBP␦, C͞EBP, and Ig͞EBP) that recognize a common DNA sequence and exhibit similar leucine zipper dimerization specificities (1). Several observations suggest that, in addition to many other regulatory functions, C͞EBPs are involved in learning and memory. For example, a C͞EBP in Aplysia (ApC͞EBP) plays an essential role in synaptic plasticity associated with long-term facilitation in sensory neurons (2). Furthermore, C͞EBP␤ and C͞EBP␦ expression is induced by pituitary adenylate cyclase-activating peptide in astrocytes (3) and amnesia, its Drosophila homolog, is known to modulate memory storage (4). Additionally, glutamate, which is implicated in synaptic mechanisms of learning and memory (5), modulates C͞EBP␤ and C͞EBP␦ expression in astrocytes (6).In the present report, we have examined the role of C͞EBP␦ (a.k.a. CRP3, NF-IL6␤, and CELF) in mice. Previous studies showed that C͞EBP␦ functions as a transcriptional activator in transactivation assays. Although low levels of C͞EBP␦ RNA are detectable in several organs of adult mice, expression is dramatically induced by bacterial lipopolysaccharide and inflammatory cytokines, suggesting a role in the acute phase and inflammatory responses. Furthermore, C͞EBP␦ expression is induced during differentiation of specific cell lines to adipocytes or granulocytes (1). C͞EBP␦ is also widely expressed in the murine nervous system (this report), similar to C͞EBP␤ (7). To address the role of C͞EBP␦ in vivo, we generated mice with a targeted deletion of the C͞EBP␦ gene. The mutant animals are viable and healthy and perform normally on several behavioral tasks, but exhibit enhanced contextual fear conditioning. These data demonstrate that a C͞EBP gene...

Coffin-Lowry Syndrome (CLS) is an X-linked syndromic form of mental retardation associated with skeletal abnormalities. It is caused by mutations of the Rsk2 gene, which encodes a growth factor regulated kinase. Gene deletion studies in mice have shown an essential role for the Rsk2 gene in osteoblast differentiation and function, establishing a causal link between Rsk2 deficiency and skeletal abnormalities of CLS. Although analyses in mice have revealed prominent expression of Rsk2 in brain structures that are essential for learning and memory, evidence at the behavioral level for an involvement of Rsk2 in cognitive function is still lacking. Here, we have examined Rsk2-deficient mice in two extensive batteries of behavioral tests, which were conducted independently in two laboratories in Zurich (Switzerland) and Orsay (France). Despite the known reduction of bone mass, all parameters of motor function were normal, confirming the suitability of Rsk2-deficient mice for behavioral testing. Rsk2-deficient mice showed a mild impairment of spatial working memory, delayed acquisition of a spatial reference memory task and long-term spatial memory deficits. In contrast, associative and recognition memory, as well as the habituation of exploratory activity were normal. Our studies also revealed mild signs of disinhibition in exploratory activity, as well as a difficulty to adapt to new test environments, which likely contributed to the learning impairments displayed by Rsk2-deficient mice. The observed behavioral changes are in line with observations made in other mouse models of human mental retardation and support a role of Rsk2 in cognitive functions.