Glucocorticoid regulates TrkB protein levels via c-Cbl dependent ubiquitination: a decrease in c-Cbl mRNA in the...

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Brain derived neurotrophic factor (BDNF) and its receptor TrkB are vital for neurodevelopment and plasticity.
• Stress and glucocorticoids disrupt TrkB signaling, with implications for prefrontal cortex function and suicidal behavior.
• Mechanisms linking glucocorticoid regulation of TrkB during neurodevelopment remain unclear.

Purpose of the Study:

• To elucidate the mechanisms by which glucocorticoids regulate TrkB during neurodevelopment.
• To investigate the role of the ubiquitin-proteasome system and c-Cbl in this regulation.
• To explore the relevance of these findings in the context of stress-related neuropsychiatric disorders and suicidal behavior.

Main Methods:

• Primary cortical neuron cultures at different developmental stages (DIV4, DIV12).
• Treatment with corticosterone, proteasome inhibitors, and analysis of TrkB and c-Cbl protein/mRNA levels.
• In vivo studies in mice (frontal cortex, hippocampus) and analysis of postmortem human brain tissue (prefrontal cortex).

Main Results:

• Acute corticosterone exposure upregulates TrkB protein levels in developing neurons via proteasome-dependent mechanisms.
• Glucocorticoid receptor (GR) and ubiquitin E3 ligase c-Cbl mediate corticosterone-induced TrkB stabilization.
• Chronic corticosterone exposure decreases TrkB and c-Cbl levels in developing neurons and in vivo, with reduced c-Cbl mRNA in suicide subjects' prefrontal cortex.

Conclusions:

• Ubiquitin-proteasome-mediated regulation of TrkB by glucocorticoids is a key mechanism influencing neuroplasticity.
• Dysregulation of this pathway, involving c-Cbl, may contribute to the pathophysiology of stress-related neuropsychiatric disorders.
• Targeting this pathway could offer therapeutic strategies for improving BDNF signaling and neuroplasticity.