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- Title
Deletion of the Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Auxiliary Subunit TRIP8b Impairs Hippocampal I<sub>h</sub> Localization and Function and Promotes Antidepressant Behavior in Mice.
- Authors
Lewis, Alan S.; Vaidya, Sachin P.; Blaiss, Cory A.; Zhiqiang Liu; Stoub, Travis R.; Brager, Darrin H.; Xiangdong Chen; 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.
- 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 ofHCN 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. Inheterologous cell sandneurons, absence of TRIP8b increased HCN subunittargeting 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. Weobserved 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 ofHCNchannels and Ih in vivo, and suggest that targeting Ih may provide a novel approach to treatment of depression.
- Subjects
NEURONS; ION channels; LYSOSOMES; HIPPOCAMPUS (Brain); MENTAL depression; MOTOR learning
- Publication
Journal of Neuroscience, 2011, Vol 31, Issue 20, p7424
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.0936-11.2011