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Cerebral Cortex Advance Access published online on February 12, 2009
Cerebral Cortex, doi:10.1093/cercor/bhp004
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© The Author 2009. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Inhibition of cAMP Response Element-Binding Protein Reduces Neuronal Excitability and Plasticity, and Triggers Neurodegeneration

Dragana Jancic, Mikel Lopez de Armentia, Luis M. Valor, Roman Olivares and Angel Barco

Instituto de Neurociencias de Alicante (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Campus de Sant Joan, 03550 Alicante, Spain

Address correspondence to Angel Barco, PhD, Instituto de Neurociencias de Alicante, Campus de Sant Joan, Apt. 18, Sant Joan d'Alacant, 03550 Alicante, Spain. Email: abarco{at}umh.es.

The cAMP-responsive element-binding protein (CREB) pathway has been involved in 2 major cascades of gene expression regulating neuronal function. The first one presents CREB as a critical component of the molecular switch that controls long-lasting forms of neuronal plasticity and learning. The second one relates CREB to neuronal survival and protection. To investigate the role of CREB-dependent gene expression in neuronal plasticity and survival in vivo, we generated bitransgenic mice expressing A-CREB, an artificial peptide with strong and broad inhibitory effect on the CREB family, in forebrain neurons in a regulatable manner. The expression of A-CREB in hippocampal neurons impaired L-LTP, reduced intrinsic excitability and the susceptibility to induced seizures, and altered both basal and activity-driven gene expression. In the long-term, the chronic inhibition of CREB function caused severe loss of neurons in the CA1 subfield as well as in other brain regions. Our experiments confirmed previous findings in CREB-deficient mutants and revealed new aspects of CREB-dependent gene expression in the hippocampus supporting a dual role for CREB-dependent gene expression regulating intrinsic and synaptic plasticity and promoting neuronal survival.

Key Words: activity-driven gene expression • CREB • neurodegeneration • neuronal excitability • synaptic plasticity

Dragana Jancic and Mikel Lopez de Armentia contributed equally to this article.


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