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The epigenetic changes of the chromatin represent an attractive molecular substrate for adaptation to the environment. We examined here the role of CREB-binding protein (CBP), a histone acetyltransferase involved in mental retardation, in the genesis and maintenance of long-lasting systemic and behavioural adaptations to environmental enrichment (EE). Morphological and behavioural analyses demonstrated that EE ameliorates deficits associated to CBP deficiency. However, CBP-deficient mice also showed a strong defect in environment-induced neurogenesis and impaired EE-mediated enhancement of spatial navigation and pattern separation ability. These defects correlated with an attenuation of the transcriptional programme induced in response to EE and with deficits in histone acetylation at the promoters of EE-regulated, neurogenesis-related genes. Additional experiments in CBP restricted and inducible knockout mice indicated that environment-induced adult neurogenesis is extrinsically regulated by CBP function in mature granule cells. Overall, our experiments demonstrate that the environment alters gene expression by impinging on activities involved in modifying the epigenome and identify CBP-dependent transcriptional neuroadaptation as an important mediator of EE-induced benefits, a finding with important implications for mental retardation therapeutics.

Costello syndrome (CS) is a rare congenital disorder caused by germline activation of H-Ras oncogenes. A mouse model of CS generated by introduction of an oncogenic Gly12Val mutation in the mouse H-Ras locus using homologous recombination in embryonic stem (ES) cells has been recently described. These mice phenocopied some of the abnormalities observed in patients with CS, including facial dysmorphia and cardiomyopathies. We investigated here their neurological and behavioral phenotype. The analysis of H-RasG12V mice revealed phenotypes that resembled the hyperemotivity, hypersensibility and cognitive impairments observed in children with CS. Stronger neurological deficits were found in the analysis of mice homozygous for this mutation than in the analysis of heterozygous mice, suggesting the existence of a gene dose effect. These mice represent the first mouse model for CS, offering an experimental tool to study the molecular and physiological alterations underlying the neurological manifestations of CS and to test new therapies aimed at preventing or ameliorating the cognitive and emotional impairments associated to this condition., This work was supported by grants from the Spanish Ministry of Education and Science to A.B. (BFU2005-00286 and SAF2005-24584-E), the European Commission to A.B. (MEXT-CT-2003-509550), the Fondo de Investigación Sanitaria to C.G. (PI042124), the Autonomous Community of Madrid to C.G. (GR/SAL/0349/2004), and Fundació La Marató de TV3 and Fundación Ramón Areces to A.B. J.V. is supported by a FPI fellowship from the Generalitat Valenciana and A.J.S. is supported by a FPU fellowship from the Spanish Ministry of Education and Science.

Long-term potentiation (LTP) and some forms of long-term memory share a number of properties, such as associativity, durability, and protein synthesis dependence. These similarities suggest that LTP could be the cellular substrate for memory ([Bliss and Collingridge, 1993][1]). The recently reported

Rubinstein-Taybi syndrome (RSTS) is a complex autosomal-dominant disease characterized by mental and growth retardation and skeletal abnormalities. A majority of the individuals diagnosed with RSTS carry heterozygous mutation in the gene CREBBP, but a small percentage of cases are caused by mutations in EP300. To investigate the contribution of p300 to RSTS pathoetiology, we carried out a comprehensive and multidisciplinary characterization of p300+/- mice. These mice exhibited facial abnormalities and impaired growth, two traits associated to RSTS in humans. We also observed abnormal gait, reduced swimming speed, enhanced anxiety in the elevated plus maze, and mild cognitive impairment during the transfer task in the water maze. These analyses demonstrate that p300+/- mice exhibit phenotypes that are reminiscent of neurological traits observed in RSTS patients, but their comparison with previous studies on CBP deficient strains also indicates that, in agreement with the most recent findings in human patients, the activity of p300 in cognition is likely less relevant or more susceptible to compensation than the activity of CBP. © 2009 Elsevier Inc. All rights reserved., This work was supported by the European Commission grant MEXT-CT-2003-509550, the Spanish Ministry of Science and Innovation Grants CSD2007-00023 and SAF2008-00611, and a grant from Fundación Ramón Areces. J.V. holds a fellowship from the Generalitat Valenciana and J.P.L.-A. a Juan de la Cierva contract supported by the Spanish Ministry of Science and Innovation.

Regulated expression of a constitutively active form of cAMP response element-binding protein (CREB), VP16-CREB, lowers the threshold for the late phase of long-term potentiation in the Schaffer collateral pathway in a de novo gene expression-independent manner, and increases the excitability and reduces afterhyperpolarization of neurons at the amygdala and the hippocampus. We explore the consequences of these changes on the consolidation of fear conditioning and find that the expression of VP16-CREB can bypass the requirement for de novo gene expression associated with long- term memory formation, suggesting that CREB-dependent gene expression is sufficient for fear memory consolidation. © 2009 Cold Spring Harbor Laboratory Press., J.V. holds a fellowship from the Generalitat Valenciana (BFPI06/316). This work was supported by European Commission grant MEXT-CT-2003-509550, Spanish MEC grants BFU2005-00286 and CSD2007-00023, Generalitat Valenciana grant AP-046/08, and grants from Fundació La Marató de TV3 and Fundación Ramón Areces.

The activation of cAMP-responsive element-binding protein (CREB)-dependent gene expression is thought to be critical for the formation of different types of long-term memory. To explore the consequences of chronic enhancement of CREB function on spatial memory in mammals, we examined spatial navigation in bitransgenic mice that express in a regulated and restricted manner a constitutively active form of CREB, VP16-CREB, in forebrain neurons. We found that chronic enhancement of CREB activity delayed the acquisition of an allocentric strategy to solve the hidden platform task. The ability to turn on and off transgene expression allowed us to dissect the role of CREB in dissociable memory processes. In mice in which transgene expression was turned on during memory acquisition, turning off the transgene reestablished the access to the memory trace, whereas in mice in which transgene expression was turned off during acquisition, turning on the transgene impaired memory expression in a reversible manner, indicating that CREB enhancement specifically interfered with the retrieval of spatial information. The defects on spatial navigation in mice with chronic enhancement of CREB function were not corrected by conditions that increased further CREB-dependent activation of hippocampal memory systems, such as housing in an enriched environment. These results along with previous findings in CREB-deficient mutants indicate that the relationship of CREB-mediated plasticity to spatial memory is an inverted-U function, and that optimal learning in the water maze requires accurate regulation of this pathway. © 2009 Cold Spring Harbor Laboratory Press., J.V. holds a fellowship from the Generalitat Valenciana (BFPI06/316), and E.B. holds a fellowship from the Gobierno Vasco. A.B. and J.V. are supported by the European Commission grant MEXT-CT-2003-509550, the Spanish MEC Grants BFU2005-00286 and CSD2007-00023, and grants from Fundació La Marató de TV3 and Fundación Ramón Areces. E.R.K, G.M., and S.V. were supported by the Howard Hughes Medical Institute and the Kavli Institute for Brain Sciences.