Deletion of the hyperpolarization-activated cyclic nucleotide-gated channel auxiliary subunit TRIP8b impairs hippocampal Ih localization and function and promotes antidepressant behavior in mice

Alan S. Lewis, Sachin P. Vaidya, Cory A. Blaiss, Zhiqiang Liu, Travis R. Stoub, Darrin H. Brager, Xiangdong Chen, Roland A. Bender, Chad M. Estep, Andrey B. Popov, Catherine E. Kang, Paul P. van Veldhoven, Douglas A. Bayliss, Daniel A. Nicholson, Craig M. Powell, Daniel Johnston, Dane M. Chetkovich

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Abstract

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 neurondendrites. 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.

Original languageEnglish (US)
Pages (from-to)7424-7440
Number of pages17
JournalJournal of Neuroscience
Volume31
Issue number20
DOIs
StatePublished - May 18 2011

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Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
Antidepressive Agents
Pyramidal Cells
Ion Channels
Neurons
Cyclic Nucleotides
Lysosomes
Knockout Mice
Membrane Potentials
Proteins
Learning
Depression
Membranes

ASJC Scopus subject areas

  • Neuroscience(all)

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Deletion of the hyperpolarization-activated cyclic nucleotide-gated channel auxiliary subunit TRIP8b impairs hippocampal Ih localization and function and promotes antidepressant behavior in mice. / Lewis, Alan S.; Vaidya, Sachin P.; Blaiss, Cory A.; Liu, Zhiqiang; Stoub, Travis R.; Brager, Darrin H.; Chen, Xiangdong; Bender, Roland A.; Estep, Chad M.; Popov, Andrey B.; Kang, Catherine E.; van Veldhoven, Paul P.; Bayliss, Douglas A.; Nicholson, Daniel A.; Powell, Craig M.; Johnston, Daniel; Chetkovich, Dane M.

In: Journal of Neuroscience, Vol. 31, No. 20, 18.05.2011, p. 7424-7440.

Research output: Contribution to journalArticle

Lewis, AS, Vaidya, SP, Blaiss, CA, Liu, Z, Stoub, TR, Brager, DH, Chen, X, Bender, RA, Estep, CM, Popov, AB, Kang, CE, van Veldhoven, PP, Bayliss, DA, Nicholson, DA, Powell, CM, Johnston, D & Chetkovich, DM 2011, 'Deletion of the hyperpolarization-activated cyclic nucleotide-gated channel auxiliary subunit TRIP8b impairs hippocampal Ih localization and function and promotes antidepressant behavior in mice', Journal of Neuroscience, vol. 31, no. 20, pp. 7424-7440. https://doi.org/10.1523/JNEUROSCI.0936-11.2011
Lewis, Alan S. ; Vaidya, Sachin P. ; Blaiss, Cory A. ; Liu, Zhiqiang ; Stoub, Travis R. ; Brager, Darrin H. ; Chen, Xiangdong ; Bender, Roland A. ; Estep, Chad M. ; Popov, Andrey B. ; Kang, Catherine E. ; van Veldhoven, Paul P. ; Bayliss, Douglas A. ; Nicholson, Daniel A. ; Powell, Craig M. ; Johnston, Daniel ; Chetkovich, Dane M. / Deletion of the hyperpolarization-activated cyclic nucleotide-gated channel auxiliary subunit TRIP8b impairs hippocampal Ih localization and function and promotes antidepressant behavior in mice. In: Journal of Neuroscience. 2011 ; Vol. 31, No. 20. pp. 7424-7440.
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abstract = "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 neurondendrites. 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.",
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AU - Blaiss, Cory A.

AU - Liu, Zhiqiang

AU - Stoub, Travis R.

AU - Brager, Darrin H.

AU - Chen, Xiangdong

AU - Bender, Roland A.

AU - Estep, Chad M.

AU - Popov, Andrey B.

AU - Kang, Catherine E.

AU - van Veldhoven, Paul P.

AU - Bayliss, Douglas A.

AU - Nicholson, Daniel A.

AU - Powell, Craig M.

AU - Johnston, Daniel

AU - Chetkovich, Dane M.

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