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.
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Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE . Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005; 62: 593–602.
Lépine J-P, Briley M . The increasing burden of depression. Neuropsychiatr Dis Treat 2011; 7: 3–7.
Krishnan V, Nestler EJ . The molecular neurobiology of depression. Nature 2008; 455: 894–902.
Duman RS, Aghajanian GK . Synaptic dysfunction in depression: potential therapeutic targets. Science 2012; 338: 68–72.
Russo SJ, Nestler EJ . The brain reward circuitry in mood disorders. Nat Rev Neurosci 2013; 14: 609–625.
Newport DJ, Carpenter LL . Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry 2015; 172: 950–966.
Papakostas GI, Ionescu DF . Towards new mechanisms: an update on therapeutics for treatment-resistant major depressive disorder. Mol Psychiatry 2015; 20: 1142–1150.
Biel M, Wahl-Schott C, Michalakis S, Zong X . Hyperpolarization-activated cation channels: from genes to function. Physio Rev 2009; 89: 847–885.
Wahl-Schott C, Biel M . HCN channels: structure, cellular regulation and physiological function. Cell Mol Life Sci 2009; 66: 470–494.
Magee JC . Dendritic hyperpolarization-activated currents modify the integrative properties of hippocampal CA1 pyramidal neurons. J Neurosci 1998; 18: 7613–7624.
Magee JC . Dendritic Ih normalizes temporal summation in hippocampal CA1 neurons. Nat Neurosci 1999; 2: 848–848.
Tsay D, Dudman JT, Siegelbaum SA . HCN1 channels constrain synaptically evoked Ca2+ spikes in distal dendrites of CA1 pyramidal neurons. Neuron 2007; 56: 1076–1089.
Santoro B, Piskorowski RA, Pian P, Hu L, Liu H, Siegelbaum SA . TRIP8b splice variants form a family of auxiliary subunits that regulate gating and trafficking of HCN channels in the brain. Neuron 2009; 62: 802–813.
Zolles G, Wenzel D, Bildl W, Schulte U, Hofmann A, Muller CS et al. Association with the auxiliary subunit PEX5R/Trip8b controls responsiveness of HCN channels to cAMP and adrenergic stimulation. Neuron 2009; 62: 814–815.
Lewis AS, Schwartz E, Chan CS, Noam Y, Shin M, Wadman WJ et al. Alternatively spliced isoforms of TRIP8b differentially control h channel trafficking and function. J Neurosci 2009; 29: 6250–6265.
Lewis AS, Vaidya SP, Blaiss CA, Liu Z, Stoub TR, Brager DH et al. Deletion of the hyperpolarization-activated cyclic nucleotide-gated channel auxiliary subunit TRIP8b impairs hippocampal Ih localization and function and promotes antidepressant behavior in mice. J Neurosci 2011; 31: 7424–7440.
Kim CS, Chang PY, Johnston D . Enhancement of dorsal hippocampal activity by knockdown of HCN1 channels leads to anxiolytic- and antidepressant-like behaviors. Neuron 2012; 75: 503–516.
Santoro B, Hu L, Liu H, Saponaro A, Pian P, Piskorowski RA et al. TRIP8b regulates HCN1 channel trafficking and gating through two distinct C-terminal interaction sites. J Neurosci 2011; 31: 4074–4086.
Han Y, Noam Y, Lewis AS, Gallagher JJ, Wadman WJ, Baram TZ et al. Trafficking and gating of hyperpolarization-activated cyclic nucleotide-gated channels are regulated by interaction with tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) and cyclic AMP at distinct sites. J Biol Chem 2011; 286: 20823–20834.
Aschauer DF, Kreuz S, Rumpel S . Analysis of transduction efficiency, tropism and axonal transport of AAV Serotypes 1, 2, 5, 6, 8 and 9 in the mouse brain. PLoS ONE 2013; 8: e76310.
Heuermann RJ, Jaramillo TC, Ying S-W, Suter BA, Lyman KA, Han Y et al. Reduction of thalamic and cortical Ih by deletion of TRIP8b produces a mouse model of human absence epilepsy. Neurobiol Dis 2016; 85: 81–92.
Piskorowski R, Santoro B, Siegelbaum SA . TRIP8b splice forms act in concert to regulate the localization and expression of HCN1 channels in CA1 pyramidal neurons. Neuron 2011; 70: 495–509.
Huang Z, Lujan R, Martinez-Hernandez J, Lewis AS, Chetkovich DM, Shah MM . TRIP8b-independent trafficking and plasticity of adult cortical presynaptic HCN1 channels. J Neurosci 2012; 32: 14835–14848.
Saponaro A, Pauleta SR, Cantini F, Matzapetakis M, Hammann C, Donadoni C et al. Structural basis for the mutual antagonism of cAMP and TRIP8b in regulating HCN channel function. Proc Natl Sci U S A 2014; 111: 14577–14582.
Friedman AK, Walsh JJ, Juarez B, Ku SM, Chaudhury D, Wang J et al. Enhancing depression mechanisms in midbrain dopamine neurons achieves homeostatic resilience. Science 2014; 344: 313–319.
Cao JL, Covington HE, Friedman AK, Wilkinson MB, Walsh JJ, Cooper DC et al. Mesolimbic dopamine neurons in the brain reward circuit mediate susceptibility to social defeat and antidepressant action. J Neurosci 2010; 30: 16453–16458.
Joëls M, Baram TZ . The neuro-symphony of stress. Nat Rev Neurosci 2009; 10: 459–466.
Qiu DL, Chu CP, Shirasaka T, Tsukino H, Nakao H, Kato K et al. Corticotrophin-releasing factor augments the IH in rat hypothalamic paraventricular nucleus parvocellular neurons in vitro. J Neurophysiol 2005; 94: 226–234.
Giesbrecht CJ, Mackay JP, Silveira HB, Urban JH, Colmers WF . Countervailing modulation of Ih by neuropeptide Y and corticotrophin-releasing factor in basolateral amygdala as a possible mechanism for their effects on stress-related behaviors. J Neurosci 2010; 30: 16970–16982.
Stepan J, Hladky F, Uribe A, Holsboer F, Schmidt MV, Eder M . High-speed imaging reveals opposing effects of chronic stress and antidepressants on neuronal activity propagation through the hippocampal trisynaptic circuit. Front Neural Circuits 2015; 9: 819.
Kallarackal AJ, Kvarta MD, Cammarata E, Jaberi L, Cai X, Bailey AM et al. Chronic stress induces a selective decrease in AMPA receptor-mediated synaptic excitation at hippocampal temporoammonic-CA1 synapses. J Neurosci 2013; 33: 15669–15674.
Cai X, Kallarackal AJ, Kvarta MD, Goluskin S, Gaylor K, Bailey AM et al. Local potentiation of excitatory synapses by serotonin and its alteration in rodent models of depression. Nat Neurosci 2013; 16: 464–472.
Han Y, Lyman K, Clutter M, Schiltz GE, Ismail QA, Prados DB et al. Identification of small-molecule inhibitors of hyperpolarization-activated cyclic nucleotide–gated channels. J Biomol Screen 2015; 20: 1124–1131.
Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature 2007; 445: 168–176.
This work was supported by National Institutes of Health Grant 2R01NS059934, R01MH106511 and R21MH104471 (D.M.C), Brain Research Foundation SG 2012-01 (D.M.C.), Chicago Biomedical Consortium HTS-004 (Y.H. and D.M.C) and National Institutes of Health Grant 2T32MH067564 (K.A.L).
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Molecular Psychiatry website
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Han, Y., Heuermann, R., Lyman, K. et al. HCN-channel dendritic targeting requires bipartite interaction with TRIP8b and regulates antidepressant-like behavioral effects. Mol Psychiatry 22, 458–465 (2017). https://doi.org/10.1038/mp.2016.99
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