Nanoscale synaptic remodeling at corticostriatal circuits predicts flexible action control

Area of Science:

• Neuroscience
• Molecular Biology
• Behavioral Science

Background:

• Synaptic plasticity underpins behavioral adaptation, but its molecular mechanisms are not fully understood.
• Understanding the molecular dynamics of synaptic plasticity is crucial for addressing behavioral rigidity and aging-related cognitive decline.

Purpose of the Study:

• To investigate the role of nanoscale synaptic remodeling in behavioral flexibility and rigidity.
• To elucidate the molecular mechanisms linking glutamatergic transmission and endocannabinoid signaling in goal-directed behavior.

Main Methods:

• Utilized Stochastic Optical Reconstruction Microscopy (STORM) for super-resolution imaging of synaptic structures.
• Examined cell-type-specific synaptic plasticity in the dorsolateral striatum of mice.
• Measured molecular abundance and nanoscale distances of key synaptic proteins.

Main Results:

• Flexible behavior correlated with increased postsynaptic metabotropic glutamate receptor 5 (mGlu5) and diacylglycerol lipase-α (DAGLα), and presynaptic CB1 receptors.
• Nanoscale reduction in distance between mGlu5 and DAGLα in postsynaptic spine heads accompanied behavioral adaptation.
• These nanoscale changes were absent in rigid behavior and aging mice, with receptor densities predicting adaptation strength.

Conclusions:

• Identified a novel nanoscale synaptic remodeling mechanism essential for behavioral flexibility.
• Demonstrated that impaired nanoscale synaptic changes contribute to behavioral rigidity and aging-related deficits.
• Highlighted the interplay between glutamatergic and endocannabinoid signaling in regulating goal-directed behavior.