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

TY - JOUR

T1 - Deletion of the hyperpolarization-activated cyclic nucleotide-gated channel auxiliary subunit TRIP8b impairs hippocampal Ih localization and function and promotes antidepressant behavior in mice.

AU - Lewis, Alan S

AU - Vaidya, Sachin P

AU - Blaiss, Cory A

AU - Liu, Zhiqiang

AU - Stoub, Travis R

AU - Brager, Darrin H

AU - Chen, Xiangdong

AU - Bender, Roland

AU - Estep, Chad M

AU - Popov, Andrey B

AU - Kang, Catherine E

AU - Veldhoven, Van

AU - Paul, P

AU - Bayliss, Douglas A

AU - Nicholson, Daniel A

AU - Powell, Craig M

AU - Johnston, Daniel

AU - Chetkovich, Dane M

PY - 2011

Y1 - 2011

N2 - 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.

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, 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.

KW - Animals

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Gene Deletion

KW - Protein Transport/genetics

KW - Cyclic Nucleotide-Gated Cation Channels/deficiency/genetics/metabolism

KW - Depression/genetics/psychology/therapy

KW - Gene Therapy/methods

KW - Hippocampus/chemistry/physiology

KW - Membrane Proteins/deficiency/metabolism/physiology

KW - Potassium Channels/deficiency/genetics/metabolism

KW - Protein Subunits/deficiency/metabolism/physiology

KW - Animals

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Gene Deletion

KW - Protein Transport/genetics

KW - Cyclic Nucleotide-Gated Cation Channels/deficiency/genetics/metabolism

KW - Depression/genetics/psychology/therapy

KW - Gene Therapy/methods

KW - Hippocampus/chemistry/physiology

KW - Membrane Proteins/deficiency/metabolism/physiology

KW - Potassium Channels/deficiency/genetics/metabolism

KW - Protein Subunits/deficiency/metabolism/physiology

M3 - SCORING: Journal article

VL - 31

SP - 7424

EP - 7440

JO - J NEUROSCI

JF - J NEUROSCI

SN - 0270-6474

IS - 20

M1 - 20

ER -