Activity-regulated circSamm50 modulates mitochondrial dynamics and spine structural plasticity

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Circular RNAs (circRNAs) are abundant in the brain, but their roles in synaptic plasticity are not well understood.
• Synaptic plasticity, essential for learning and memory, involves structural changes at synapses.
• Mitochondrial function is critical for neuronal energy supply and synaptic activity.

Purpose of the Study:

• To identify and characterize plasticity-induced circRNAs in the brain.
• To investigate the functional role of circSamm50 in neuronal plasticity and mitochondrial regulation.
• To elucidate the molecular mechanism linking circRNAs, mitochondria, and synaptic structure.

Main Methods:

• Primary hippocampal neuron culture and chemical long-term potentiation induction.
• Identification and quantification of circRNAs using RNA sequencing.
• CRISPR-Cas13 system for acute circRNA depletion.
• Mitochondrial morphology, transport, and bioenergetic assays.
• Electrophysiology and two-photon glutamate uncaging for synaptic plasticity assessment.

Main Results:

• A plasticity-induced circRNA, circSamm50, was identified and found to be upregulated following chemical long-term potentiation.
• circSamm50 sequesters miR-186-5p, stabilizing Samm50 mRNA and influencing mitochondrial gene regulation.
• Depletion of circSamm50 led to disrupted mitochondrial morphology, transport, and bioenergetics.
• Loss of circSamm50 impaired synaptic transmission, reduced spine density, and compromised activity-dependent structural plasticity.

Conclusions:

• circSamm50 is a plasticity-modulated circRNA that coordinates mitochondrial function with activity-dependent spine remodeling.
• This study reveals a novel mechanism where circRNAs couple metabolic control to synapse function and structural plasticity.
• circSamm50 represents a potential therapeutic target for neurological disorders involving synaptic dysfunction and mitochondrial defects.