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The Journal of Neuroscience, December 12, 2007, 27(50):13909-13918; doi:10.1523/JNEUROSCI.3850-07.2007

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 Previous Article

Development/Plasticity/Repair
cAMP Response Element-Binding Protein-Mediated Gene Expression Increases the Intrinsic Excitability of CA1 Pyramidal Neurons

Mikel Lopez de Armentia,¹ Dragana Jancic,¹ Roman Olivares,¹ Juan M. Alarcon,² Eric R. Kandel,^2,3 and Angel Barco¹

¹Instituto de Neurociencias de Alicante (Universidad Miguel Hernández–Consejo Superior de Investigaciones Científicas), Campus de Sant Joan, Sant Joan d'Alacant, 03550 Alicante, Spain, and ²Kavli Institute and ³Howard Hughes Medical Institute, Center for Neurobiology and Behavior, College of Physicians and Surgeons of Columbia University, New York, New York 10032

Correspondence should be addressed to Angel Barco, Instituto de Neurociencias de Alicante (Universidad Miguel Hernández–Consejo Superior de Investigaciones Científicas), Campus de Sant Joan, Apartado 18, Sant Joan d'Alacant, 03550 Alicante, Spain. Email: abarco{at}umh.es

To investigate the role of CREB-mediated gene expression on the excitability of CA1 pyramidal neurons, we obtained intracellular recordings from pyramidal neurons of transgenic mice expressing a constitutively active form of CREB, VP16–CREB, in a regulated and restricted manner. We found that transgene expression increased the neuronal excitability and inhibited the slow and medium afterhyperpolarization currents. These changes may contribute to the reduced threshold for LTP observed in these mice. When strong transgene expression was turned on for prolonged period of time, these mice also showed a significant loss of hippocampal neurons and sporadic epileptic seizures. These deleterious effects were dose dependent and could be halted, but not reversed by turning off transgene expression. Our experiments reveal a new role for hippocampal CREB-mediated gene expression, identify the slow afterhyperpolarization as a primary target of CREB action, provide a new mouse model to investigate temporal lobe epilepsy and associated neurodegeneration, and illustrate the risks of cell death associated to a sustained manipulation of this pathway. As a result, our study has important implications for both the understanding of the cellular bases of learning and memory and the consideration of therapies targeted to the CREB pathway.

Key words: AHP; CREB; excitability; excitotoxicity; learning and memory; synaptic plasticity

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Received Aug. 23, 2007; revised Oct. 25, 2007; accepted Oct. 27, 2007.

Correspondence should be addressed to Angel Barco, Instituto de Neurociencias de Alicante (Universidad Miguel Hernández–Consejo Superior de Investigaciones Científicas), Campus de Sant Joan, Apartado 18, Sant Joan d'Alacant, 03550 Alicante, Spain. Email: abarco{at}umh.es

This article has been cited by other articles:

				B. M. McKay, E. A. Matthews, F. A. Oliveira, and J. F. Disterhoft Intrinsic Neuronal Excitability Is Reversibly Altered by a Single Experience in Fear Conditioning J Neurophysiol, November 1, 2009; 102(5): 2763 - 2770. [Abstract] [Full Text] [PDF]

				D. Jancic, M. Lopez de Armentia, L. M. Valor, R. Olivares, and A. Barco Inhibition of cAMP Response Element-Binding Protein Reduces Neuronal Excitability and Plasticity, and Triggers Neurodegeneration Cereb Cortex, November 1, 2009; 19(11): 2535 - 2547. [Abstract] [Full Text] [PDF]

				J. Viosca, M. Lopez de Armentia, D. Jancic, and A. Barco Enhanced CREB-dependent gene expression increases the excitability of neurons in the basal amygdala and primes the consolidation of contextual and cued fear memory Learn. Mem., February 23, 2009; 16(3): 193 - 197. [Abstract] [Full Text] [PDF]

				J. Viosca, G. Malleret, R. Bourtchouladze, E. Benito, S. Vronskava, E. R. Kandel, and A. Barco Chronic enhancement of CREB activity in the hippocampus interferes with the retrieval of spatial information Learn. Mem., February 23, 2009; 16(3): 198 - 209. [Abstract] [Full Text] [PDF]

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