BDNF pro-peptide regulates dendritic spines via caspase-3

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Brain-derived neurotrophic factor (BDNF) precursor (proBDNF) is processed into mature BDNF (mBDNF) and a pro-peptide.
• The function of the BDNF pro-peptide remains largely uncharacterized.
• Specific antibodies were developed to detect the cleaved BDNF pro-peptide.

Purpose of the Study:

• To investigate the function of the BDNF pro-peptide.
• To explore the regulation and cellular effects of extracellular BDNF pro-peptide.

Main Methods:

• Development of a specific antibody for cleaved BDNF pro-peptide.
• Neuronal depolarization to assess activity-dependent release.
• Treatment of mature hippocampal neurons with BDNF pro-peptide.
• Assessment of dendritic spine density.
• Pharmacological inhibition and genetic knockdown of caspase-3.
• Mitochondrial morphology and cytochrome c release analysis.

Main Results:

• Neuronal depolarization significantly increased extracellular BDNF pro-peptide levels.
• BDNF pro-peptide exposure reduced dendritic spine density in cultured hippocampal neurons.
• The reduction in spine density was mediated by caspase-3 activation.
• BDNF pro-peptide promoted mitochondrial elongation and cytosolic cytochrome c release, indicating involvement of the mitochondrial-caspase-3 pathway.

Conclusions:

• BDNF pro-peptide is regulated in an activity-dependent manner.
• BDNF pro-peptide acts as a negative regulator of neuronal structure, specifically reducing dendritic spine density.
• The mitochondrial-caspase-3 pathway is implicated in the cellular effects of BDNF pro-peptide.
• These findings suggest a novel role for BDNF pro-peptide in modulating neuronal function.