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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.
Molecular Psychiatry
|April 19, 2017
Summary
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.