Depression refractory to medical treatment is seen in over half of patients with Major Depressive Disorder (MDD) and is associated with high rates of disability and suicide. Most existing treatments for MDD target brain pathways involving the monoaminergic neurotransmitters serotonin, norepinephrine and dopamine. Because of high rates of treatment resistance, new therapies focusing on non-monoaminergic mechanisms could lead to major breakthroughs, saving many lives. One region of the brain altered in patients with depression is the hippocampus, which is also an important target for the action of antidepressants. Within the hippocampus, an ion channel called the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel helps control neuronal excitability. HCN channels mediate a current (Ih) that is critical for processing synaptic signals between neurons. The HCN channel is expressed at increasingly higher levels along the length of neuronal dendrites, and this subcellular localization is important for the HCN channel's role in signal processing. HCN channel localization is tightly regulated by its auxiliary subunit, TRIP8b (tetratricopeptide repea-containing Rab8b-interacting protein). Our lab recently showed that genetic deletion of HCN channel subunits leads to an antidepressant-like phenotype in mice. Furthermore, others found that decreasing HCN1 in the hippocampus using inhibitory RNA produced similar antidepressant effects, suggesting HCN channel function could be targeted to treat depression. HCN channels are crucial for many functions in the brain and heart, thus pharmaceutical approaches to inhibiting HCN channels could produce unwanted side effects. In contrast, anatomically targeted gene therapy using viral vectors offers the benefit of controlling exactly when and where genes are expressed. In preliminary studies, we found that viral infection of the hippocampus using an adeno-associated virus (AAV) engineered to prevent normal trafficking of HCN subunits in hippocampal neurons (but not control AAV expressing green fluorescent protein) markedly reduced depression-like behavior in tests that screen for antidepressant activity. We thus hypothesize that viral vector-mediated gene therapy to suppress HCN channels in the dorsal hippocampus is an effective treatment for depression. To test this hypothesis, we will use immunohistochemical, biochemical, electrophysiological and behavioral studies to complete the following specific aims: 1) Determine if viral gene therapy targeting HCN channels can produce specific and lasting antidepressant-like effects in mice, and 2) Determine if viral gene therapy targeting HCN channels can effectively eliminate depression-like behaviors in genetic and environmental mouse models of depression. Overall, our proposed work will evaluate a novel target and innovative treatment strategy for depression distinct from all current therapy, with an ultimate goal of translating this therapy to future studies in human patients with depression refractory to existing treatments.

Public Health Relevance

Existing antidepressants target a narrow group of brain chemicals such as serotonin, but these treatments fail in up to half of depressed patients. Recent studies have shown that a molecule in the brain called the HCN channel may play an important role in depression. This project will test whether gene therapy to reduce brain HCN channels can cure depression-like behavior in mouse models of depression, with the ultimate goal of developing a gene therapy strategy to cure human patients with treatment-resistant depression.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
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Winsky, Lois M
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Northwestern University at Chicago
Schools of Medicine
United States
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Fisher, Daniel W; Han, Ye; Lyman, Kyle A et al. (2018) HCN channels in the hippocampus regulate active coping behavior. J Neurochem 146:753-766
Yun, Sanghee; Reynolds, Ryan P; Petrof, Iraklis et al. (2018) Stimulation of entorhinal cortex-dentate gyrus circuitry is antidepressive. Nat Med 24:658-666
Lyman, Kyle A; Han, Ye; Heuermann, Robert J et al. (2017) Allostery between two binding sites in the ion channel subunit TRIP8b confers binding specificity to HCN channels. J Biol Chem 292:17718-17730
Lyman, Kyle A; Han, Ye; Chetkovich, Dane M (2017) Animal models suggest the TRIP8b-HCN interaction is a therapeutic target for major depressive disorder. Expert Opin Ther Targets 21:235-237
Han, Y; Heuermann, R J; Lyman, K A et al. (2017) HCN-channel dendritic targeting requires bipartite interaction with TRIP8b and regulates antidepressant-like behavioral effects. Mol Psychiatry 22:458-465
Han, Ye; Lyman, Kyle A; Clutter, Matt et al. (2016) Method for Identifying Small Molecule Inhibitors of the Protein-protein Interaction Between HCN1 and TRIP8b. J Vis Exp :
Han, Ye; Lyman, Kyle; Clutter, Matt et al. (2015) Identification of Small-Molecule Inhibitors of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels. J Biomol Screen 20:1124-31