Activity-dependent rapid local RhoA synthesis is required for hippocampal synaptic plasticity

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Dendritic protein synthesis and actin cytoskeleton dynamics are crucial for hippocampal long-term potentiation (LTP) and memory.
• The precise interplay between these processes during LTP consolidation is not fully understood.

Purpose of the Study:

• To elucidate the temporal and spatial relationship between dendritic protein synthesis and actin cytoskeleton reorganization in hippocampal LTP.
• To identify key molecular players, such as RhoA, involved in this process.

Main Methods:

• Treatment of adult rat hippocampal slices with BDNF or TEA to induce chemical LTP.
• Assessment of RhoA protein levels, activity, and localization in dendritic spines.
• Inhibition of protein synthesis using mammalian target of rapamycin (mTOR) inhibitors.
• Intrahippocampal injections of RhoA antisense oligodeoxynucleotides.
• Application of calpain inhibitors (general and isoform-specific).

Main Results:

• BDNF and TEA rapidly increased RhoA protein levels in CA3 and CA1 dendritic spines, dependent on de novo protein synthesis regulated by mTOR.
• RhoA upregulation, cofilin phosphorylation, and actin polymerization induced by BDNF were blocked by protein synthesis inhibitors.
• RhoA antisense oligodeoxynucleotides prevented TBS-induced RhoA increase and LTP consolidation.
• Calpain inhibitors sustained RhoA levels and prolonged BDNF/TEA effects on actin polymerization.
• Calpain-2 mediated RhoA synthesis, while calpain-1 mediated its degradation.

Conclusions:

• A novel mechanism links dendritic protein synthesis to actin cytoskeleton reorganization in hippocampal dendritic spines during LTP consolidation.
• RhoA acts as a key mediator in this pathway, with its synthesis and degradation tightly regulated by calpains.
• This finding provides new insights into the molecular basis of synaptic plasticity and memory formation.