PT  - JOURNAL ARTICLE
AU  - Alan S. Lewis
AU  - Sachin P. Vaidya
AU  - Cory A. Blaiss
AU  - Zhiqiang Liu
AU  - Travis R. Stoub
AU  - Darrin H. Brager
AU  - Xiangdong Chen
AU  - Roland A. Bender
AU  - Chad M. Estep
AU  - Andrey B. Popov
AU  - Catherine E. Kang
AU  - Paul P. Van Veldhoven
AU  - Douglas A. Bayliss
AU  - Daniel A. Nicholson
AU  - Craig M. Powell
AU  - Daniel Johnston
AU  - Dane M. Chetkovich
TI  - Deletion of the Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Auxiliary Subunit TRIP8b Impairs Hippocampal <em>I</em><sub>h</sub> Localization and Function and Promotes Antidepressant Behavior in Mice
AID  - 10.1523/JNEUROSCI.0936-11.2011
DP  - 2011 May 18
TA  - The Journal of Neuroscience
PG  - 7424--7440
VI  - 31
IP  - 20
4099  - http://www.jneurosci.org/content/31/20/7424.short
4100  - http://www.jneurosci.org/content/31/20/7424.full
SO  - J. Neurosci.2011 May 18; 31
AB  - Output properties of neurons are greatly shaped by voltage-gated ion channels, whose biophysical properties and localization within axodendritic compartments serve to significantly transform the original input. The hyperpolarization-activated current, Ih, is mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and plays a fundamental role in influencing neuronal excitability by regulating both membrane potential and input resistance. In neurons such as cortical and hippocampal pyramidal neurons, the subcellular localization of HCN channels plays a critical functional role, yet mechanisms controlling HCN channel trafficking are not fully understood. Because ion channel function and localization are often influenced by interacting proteins, we generated a knock-out mouse lacking the HCN channel auxiliary subunit, tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b). Eliminating expression of TRIP8b dramatically reduced Ih expression in hippocampal pyramidal neurons. Loss of Ih-dependent membrane voltage properties was attributable to reduction of HCN channels on the neuronal surface, and there was a striking disruption of the normal expression pattern of HCN channels in pyramidal neuron dendrites. In heterologous cells and neurons, absence of TRIP8b increased HCN subunit targeting to and degradation by lysosomes. Mice lacking TRIP8b demonstrated motor learning deficits and enhanced resistance to multiple tasks of behavioral despair with high predictive validity for antidepressant efficacy. We observed similar resistance to behavioral despair in distinct mutant mice lacking HCN1 or HCN2. These data demonstrate that interaction with the auxiliary subunit TRIP8b is a major mechanism underlying proper expression of HCN channels and Ih in vivo, and suggest that targeting Ih may provide a novel approach to treatment of depression.