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Perisomatic changes in h-channels regulate depressive behaviors following chronic unpredictable stress
C S Kim1, D H Brager1, D Johnston1
1Center for Learning and Memory and Department of Neuroscience, University of Texas at Austin, Austin, TX, USA.
Insights
Chronic unpredictable stress increases HCN1 protein and Ih currents in dorsal CA1 neurons, contributing to depression-like behaviors. Reducing these currents alleviates these deficits, suggesting HCN channels as a therapeutic target for major depressive disorder.
Area of Science:
- Neuroscience
- Molecular Biology
- Psychiatry
Background:
- Chronic stress is a known risk factor for developing depression.
- HCN1 protein and its associated Ih currents are implicated in antidepressant effects.
- Alterations in h-channels in depression models remain largely unexplored.
Purpose of the Study:
- To investigate the role of HCN1 protein and Ih currents in a rat model of depression.
- To determine if chronic unpredictable stress (CUS) affects h-channel function in the hippocampus.
- To explore HCN channels as a potential therapeutic target for major depressive disorder.
Main Methods:
- Utilized chronic unpredictable stress (CUS) in a rat model of major depressive disorder.
- Measured HCN1 protein expression and Ih-sensitive physiological parameters in dorsal and ventral CA1 regions.
- Employed cell-attached patch clamp recordings to assess neuronal excitability.
- Used shRNA-HCN1 to reduce dorsal CA1 Ih and observed behavioral outcomes.
- Administered thapsigargin, a SERCA pump inhibitor, to dorsal CA1 to induce anxiogenic-like behaviors.
Main Results:
- CUS significantly increased perisomatic HCN1 protein expression and Ih in dorsal CA1 neurons, but not ventral CA1.
- Patch clamp recordings confirmed elevated perisomatic Ih in dorsal CA1 neurons post-CUS.
- Reducing dorsal CA1 Ih via shRNA-HCN1 prevented CUS-induced behavioral deficits.
- Thapsigargin infusion in dorsal CA1 mimicked CUS effects, causing anxiogenic-like behaviors and increased Ih.
Conclusions:
- CUS, unlike acute stress, elevates perisomatic Ih in dorsal CA1 neurons.
- Increased HCN channel activity in dorsal CA1 contributes to depression-like behaviors.
- HCN channels are a promising therapeutic target for treating major depressive disorder.
Abstract:
Chronic stress can be a precipitating factor in the onset of depression. Lentiviral-mediated knockdown of HCN1 protein expression and reduction of functional Ih produce antidepressant behavior. However, whether h-channels are altered in an animal model of depression is not known. We found that perisomatic HCN1 protein expression and Ih-sensitive physiological measurements were significantly increased in dorsal but not in ventral CA1 region/neurons following chronic unpredictable stress (CUS), a widely accepted model for major depressive disorder. Cell-attached patch clamp recordings confirmed that perisomatic Ih was increased in dorsal CA1 neurons following CUS. Furthermore, when dorsal CA1 Ih was reduced by shRNA-HCN1, the CUS-induced behavioral deficits were prevented. Finally, rats infused in the dorsal CA1 region with thapsigargin, an irreversible inhibitor of the SERCA pump, exhibited anxiogenic-like behaviors and increased Ih, similar to that observed following CUS. Our results suggest that CUS, but not acute stress, leads to an increase in perisomatic Ih in dorsal CA1 neurons and that HCN channels represent a potential target for the treatment of major depressive disorder.