title: HCN-channel dendritic targeting requires bipartite interaction with TRIP8b and regulates antidepressant-like behavioral effects.
abstract: Major depressive disorder (MDD) is a prevalent psychiatric condition with limited therapeutic options beyond monoaminergic therapies. Although effective in some individuals, many patients fail to respond adequately to existing treatments, and new pharmacologic targets are needed. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate excitability in neurons, and blocking HCN channel function has been proposed as a novel antidepressant strategy. However, systemic blockade of HCN channels produces cardiac effects that limit this approach. Knockout (KO) of the brain-specific HCN-channel auxiliary subunit tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) also produces antidepressant-like behavioral effects and suggests that inhibiting TRIP8b function could produce antidepressant-like effects without affecting the heart. We examined the structural basis of TRIP8b-mediated HCN-channel trafficking and its relationship with antidepressant-like behavior using a viral rescue approach in TRIP8b KO mice. We found that restoring TRIP8b to the hippocampus was sufficient to reverse the impaired HCN-channel trafficking and antidepressant-like behavioral effects caused by TRIP8b KO. Moreover, we found that hippocampal expression of a mutated version of TRIP8b further impaired HCN-channel trafficking and increased the antidepressant-like behavioral phenotype of TRIP8b KO mice. Thus, modulating the TRIP8b-HCN interaction bidirectionally influences channel trafficking and antidepressant-like behavior. Overall, our work suggests that small-molecule inhibitors of the interaction between TRIP8b and HCN should produce antidepressant-like behaviors and could represent a new paradigm for the treatment of MDD.
authors.affiliation: Davee Department of Neurology and Clinical Neurosciences, Northwestern University, Chicago, IL, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Han
authors.affiliation: Davee Department of Neurology and Clinical Neurosciences, Northwestern University, Chicago, IL, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Heuermann
authors.affiliation: Davee Department of Neurology and Clinical Neurosciences, Northwestern University, Chicago, IL, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Lyman
authors.affiliation: Davee Department of Neurology and Clinical Neurosciences, Northwestern University, Chicago, IL, USA.
authors.forename: D
authors.initials: D
authors.lastname: Fisher
authors.affiliation: Davee Department of Neurology and Clinical Neurosciences, Northwestern University, Chicago, IL, USA.
authors.forename: Q-A
authors.initials: QA
authors.lastname: Ismail
authors.affiliation: Davee Department of Neurology and Clinical Neurosciences, Northwestern University, Chicago, IL, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Chetkovich
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000378:metabolism; D056547:CA1 Region, Hippocampal / Q000378:metabolism; D054815:Cyclic Nucleotide-Gated Cation Channels; D003712:Dendrites / Q000378:metabolism; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D000074401:Peroxins; D015221:Potassium Channels / Q000235:genetics; D011485:Protein Binding; D021381:Protein Transport / Q000502:physiology
chemical_list: D000928:Antidepressive Agents; D054815:Cyclic Nucleotide-Gated Cation Channels; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D008565:Membrane Proteins; D000074401:Peroxins; C501732:Pex5l protein, mouse; D015221:Potassium Channels