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

Publisher: Society for Neuroscience Country of Publication: United States NLM ID: 8102140 Publication Model: Print Cited Medium: Internet ISSN: 1529-2401 (Electronic) Linking ISSN: 02706474 NLM ISO Abbreviation: J Neurosci Subsets: MEDLINE

Publication: Washington, DC : Society for Neuroscience
Original Publication: [Baltimore, Md.] : The Society, c1981-

Gene Deletion*; Cyclic Nucleotide-Gated Cation Channels/*deficiency ; Cyclic Nucleotide-Gated Cation Channels/*metabolism ; Depression/*genetics ; Hippocampus/*physiology ; Membrane Proteins/*deficiency ; Membrane Proteins/*metabolism ; Potassium Channels/*deficiency ; Potassium Channels/*metabolism ; Protein Subunits/*metabolism; Animals ; Cyclic Nucleotide-Gated Cation Channels/genetics ; Depression/psychology ; Depression/therapy ; Genetic Therapy/methods ; Hippocampus/chemistry ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels ; Membrane Proteins/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Peroxins ; Potassium Channels/genetics ; Protein Subunits/deficiency ; Protein Subunits/physiology ; Protein Transport/genetics

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, I(h), 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 I(h) expression in hippocampal pyramidal neurons. Loss of I(h)-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 I(h) in vivo, and suggest that targeting I(h) may provide a novel approach to treatment of depression.

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F30 NS064757 United States NS NINDS NIH HHS; R01 MH081164-03 United States MH NIMH NIH HHS; NS059934 United States NS NINDS NIH HHS; NS05595 United States NS NINDS NIH HHS; R01 MH081164-01A2 United States MH NIMH NIH HHS; R01 AG017139 United States AG NIA NIH HHS; R56 AG017139 United States AG NIA NIH HHS; RF1 AG017139 United States AG NIA NIH HHS; R01 HD069560-01 United States HD NICHD NIH HHS; R01 NS059934 United States NS NINDS NIH HHS; AS2126 United States Autism Speaks; R01 MH081164-04 United States MH NIMH NIH HHS; R21 HD065290-01 United States HD NICHD NIH HHS; K08 NS041956-04 United States NS NINDS NIH HHS; R01 MH081164-02 United States MH NIMH NIH HHS; K99 AG031574 United States AG NIA NIH HHS; R00 AG031574 United States AG NIA NIH HHS; K08 NS041956-05 United States NS NINDS NIH HHS; R01 NS059934-04 United States NS NINDS NIH HHS; MH048432 United States MH NIMH NIH HHS; K08 NS041956-03 United States NS NINDS NIH HHS; AG017139 United States AG NIA NIH HHS; R01 MH081164 United States MH NIMH NIH HHS; NS064757 United States NS NINDS NIH HHS; R01 NS059934-03 United States NS NINDS NIH HHS; R01 MH048432 United States MH NIMH NIH HHS; MH081164 United States MH NIMH NIH HHS; AG031574 United States AG NIA NIH HHS; R21 HD065290 United States HD NICHD NIH HHS; R01 MH081164-05 United States MH NIMH NIH HHS; R01 HD069560-02 United States HD NICHD NIH HHS; R21 HD065290-02 United States HD NICHD NIH HHS; HD065290 United States HD NICHD NIH HHS; R01 GM066181 United States GM NIGMS NIH HHS

0 (Cyclic Nucleotide-Gated Cation Channels)
0 (Hcn1 protein, mouse)
0 (Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels)
0 (Membrane Proteins)
0 (Peroxins)
0 (Pex5l protein, mouse)
0 (Potassium Channels)
0 (Protein Subunits)

Date Created: 20110520 Date Completed: 20110721 Latest Revision: 20240718

20240718

PMC3169171

10.1523/JNEUROSCI.0936-11.2011

21593326