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J. Biol. Chem., Vol. 282, Issue 45, 33168-33180, November 9, 2007

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Activity-dependent Regulation of h Channel Distribution in Hippocampal CA1 Pyramidal Neurons^*

Minyoung Shin and Dane M. Chetkovich¹

From the Davee Department of Neurology and Clinical Neurosciences and Department of Physiology, Feinberg School of Medicine, Northwestern University Medical School, Chicago, Illinois 60611

The hyperpolarization-activated cation current, I_h, plays an important role in regulating intrinsic neuronal excitability in the brain. In hippocampal pyramidal neurons, I_h is mediated by h channels comprised primarily of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel subunits, HCN1 and HCN2. Pyramidal neuron h channels within hippocampal area CA1 are remarkably enriched in distal apical dendrites, and this unique distribution pattern is critical for regulating dendritic excitability. We utilized biochemical and immunohistochemical approaches in organotypic slice cultures to explore factors that control h channel localization in dendrites. We found that distal dendritic enrichment of HCN1 is first detectable at postnatal day 13, reaching maximal enrichment by the 3rd postnatal week. Interestingly we found that an intact entorhinal cortex, which projects to distal dendrites of CA1 but not area CA3, is critical for the establishment and maintenance of distal dendritic enrichment of HCN1. Moreover blockade of excitatory neurotransmission using tetrodotoxin, 6-cyano-7-nitroquinoxaline-2,3-dione, or 2-aminophosphonovalerate redistributed HCN1 evenly throughout the dendrite without significant changes in protein expression levels. Inhibition of calcium/calmodulin-dependent protein kinase II activity, but not p38 MAPK, also redistributed HCN1 in CA1 pyramidal neurons. We conclude that activation of ionotropic glutamate receptors by excitatory temporoammonic pathway projections from the entorhinal cortex establishes and maintains the distribution pattern of HCN1 in CA1 pyramidal neuron dendrites by activating calcium/calmodulin-dependent protein kinase II-mediated downstream signals.

Received for publication, May 7, 2007 , and in revised form, August 6, 2007.

^* This work was supported by National Institutes of Health Grant R21 NS052595 and grants from the Partnership for Pediatric Epilepsy Research, which includes the American Epilepsy Society, the Epilepsy Foundation, The Epilepsy Project, Fight Against Childhood Epilepsy and Seizures, and Parents Against Childhood Epilepsy. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-3.

¹ To whom correspondence should be addressed: Davee Dept. of Neurology and Clinical Neuroscience, Northwestern University Medical School, 303 East Chicago Ave., Ward 10-201, Chicago, IL 60611-3008. Tel.: 312-503-4362; Fax: 312-503-0872; E-mail: d-chetkovich{at}northwestern.edu.

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