Summary: New research shows that reducing a specific group of proteins in the brain decreases depression-like behavior in mice, pointing to a promising target for future antidepressant therapies.
Source: Northwestern University.
Manipulating a novel molecular target could lead to new treatments for depression
Researchers at Northwestern Medicine report that targeted manipulation of HCN channels in the hippocampus can produce antidepressant-like effects in mouse models. Using a gene therapy approach to reduce the function of HCN channels, the team observed a significant decrease in depression-like behaviors. These findings suggest a potential new therapeutic route for people with major depressive disorder who do not respond to existing medications.
“Current antidepressant drugs help many patients but fail for others or lose effectiveness over time,” said Dr. Dane Chetkovich, senior author and professor of neurology and physiology at Northwestern University Feinberg School of Medicine. “There is a real need for new therapeutic strategies that target mechanisms beyond traditional monoamine systems.”
The study is published in Molecular Psychiatry.
Most approved antidepressants work by increasing monoamine neurotransmitters such as serotonin, dopamine and norepinephrine. Because these treatments are ineffective for a substantial subset of patients, researchers have been investigating alternative cellular and circuit-level mechanisms that could be exploited for new drugs or biologic therapies.
Prior work from Chetkovich’s lab and others implicated the hippocampus—a brain region critical for learning, memory and emotional regulation—in depression-related behaviors. Those studies identified changes in hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, proteins that influence the electrical excitability of neurons and are also found in the heart. Altered HCN channel function in hippocampal neurons appeared to correlate with behavioral changes linked to depression.
In the current study, investigators used a nontoxic viral vector to deliver a gene that suppresses HCN channel function specifically within hippocampal neurons of mice. After surgical delivery of the gene therapy, mice displayed behavioral responses consistent with effective antidepressant treatment.
Behavioral testing focused on widely used paradigms that measure persistence and escape behavior in stressful situations. For example, the researchers measured how long mice would actively seek escape before exhibiting behavioral despair, an industry-standard screening test that correlates with antidepressant efficacy.
“When HCN channel function was reduced in the hippocampus, mice showed the same kinds of improvement as seen with established antidepressants,” Chetkovich said. By contrast, experimentally increasing HCN channel function eliminated the antidepressant-like effect, supporting a causal relationship between HCN activity and mood-related behavior.
The molecular mechanism behind this effect involves the brain-specific auxiliary subunit TRIP8b, which controls the dendritic targeting and trafficking of HCN channels. Previous genetic studies revealed that knockout of TRIP8b produces antidepressant-like behavior in mice without the cardiac side effects that would arise from systemic HCN blockade. In this study, viral manipulation of TRIP8b–HCN interactions in the hippocampus bidirectionally regulated both channel trafficking and antidepressant-like behavior.
“This work not only identifies a new treatment target for depression, it maps the molecular interactions that must be altered to achieve an antidepressant effect and provides viral tools to test those manipulations,” said Chetkovich, who directs Feinberg’s Medical Scientist Training Program.
Looking ahead, the team is developing strategies to translate these findings toward human therapies. Ongoing efforts include adapting viral gene therapy approaches for potential clinical use and screening for small molecules that selectively disrupt the TRIP8b–HCN interaction in the brain, which could yield an oral medication that targets hippocampal HCN channels without cardiac side effects.
Other Northwestern authors on the study include Ye Han, Robert Heuermann, Kyle Lyman, Daniel Fisher and Quratul-Ain Ismail.
Funding: The work was supported by National Institutes of Health grants 2R01NS059934, R01MH106511, R21MH104471 and 2T32MH067564, Brain Research Foundation grant SG 2012-01 and Chicago Biomedical Consortium grant HTS-004.
Source: Northwestern University. Original research: Han Y., Heuermann R.J., Lyman K.A., Fisher D., Ismail Q.-A., and Chetkovich D.M., “HCN-channel dendritic targeting requires bipartite interaction with TRIP8b and regulates antidepressant-like behavioral effects,” Molecular Psychiatry, published online July 12, 2016 (doi:10.1038/mp.2016.99).
HCN-channel dendritic targeting requires bipartite interaction with TRIP8b and regulates antidepressant-like behavioral effects
Major depressive disorder (MDD) is a common psychiatric illness with limited treatment options beyond monoaminergic therapies. Many patients do not achieve remission with current drugs, underscoring the need for novel pharmacologic targets. HCN channels regulate neuronal excitability, and blocking HCN function has been proposed as a potential antidepressant strategy; however, systemic HCN blockade can cause cardiac side effects. The brain-specific auxiliary subunit TRIP8b regulates HCN-channel trafficking, and TRIP8b knockout produces antidepressant-like behavior without cardiac effects. Using viral rescue and manipulation in TRIP8b knockout mice, the study demonstrates that restoring TRIP8b to the hippocampus reverses altered HCN trafficking and the antidepressant-like phenotype, while expression of a mutant TRIP8b further disrupts trafficking and enhances the antidepressant-like effect. These results indicate that modulating the TRIP8b–HCN interaction in hippocampal neurons bidirectionally influences channel localization and mood-related behavior, suggesting that small-molecule inhibitors of the TRIP8b–HCN interaction could represent a novel class of antidepressant therapies.
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