Inhibition of cAMP response element-binding protein reduces neuronal excitability and plasticity, and triggers neurodegeneration.
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.
Jancic
Dragana
D
Instituto de Neurociencias de Alicante (Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas), Campus de Sant Joan, 03550 Alicante, Spain.
Lopez de Armentia
Mikel
M
Valor
Luis M
LM
Olivares
Roman
R
Barco
Angel
A
D000818:Animals; D001921:Brain / Q000378:metabolism*; D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009433:Neural Inhibition; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D009473:Neuronal Plasticity; D009474:Neurons; D009435:Synaptic Transmission
D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse