Presynaptic Rac1 in the hippocampus selectively regulates working memory.

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• Rac1, a small GTPase, is involved in actin remodeling and signaling.
• Rac1 signaling influences learning, memory, and synaptic plasticity.
• The precise roles of Rac1 in different cognitive functions and plasticity remain unclear.

Purpose of the Study:

• To investigate the distinct roles of Rac1 in presynaptic and postsynaptic compartments.
• To elucidate the molecular mechanisms underlying presynaptic Rac1 function in cognition.
• To identify proteins and post-translational modifications associated with presynaptic Rac1 signaling.

Main Methods:

• Utilized a genetically encoded Rac1 inhibitor targeted to presynaptic terminals.
• Employed mass spectrometry to analyze the presynaptic proteomic and post-translational landscape.
• Examined changes in synaptic vesicle distribution, morphology, and postsynaptic ultrastructure.

Main Results:

• Presynaptic Rac1 inhibition selectively impaired spatial working memory in mice.
• Postsynaptic Rac1 inhibition affected longer-term cognitive processes.
• Identified serine/threonine kinases and phosphorylated proteins regulating synaptic vesicles at active presynaptic Rac1 sites.
• Observed alterations in synaptic vesicle dynamics and postsynaptic structures.

Conclusions:

• Rac1 signaling plays a critical, previously unrecognized, presynaptic role in cognitive processes.
• Distinct presynaptic and postsynaptic functions of Rac1 contribute to different forms of memory and plasticity.
• Presynaptic Rac1 regulates synaptic vesicle function, impacting cognitive performance.