Astrocyte-Secreted Neurocan Controls Inhibitory Synapse Formation and Function.

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• Astrocytes are crucial for synapse development, secreting proteins that guide synapse formation and maturation.
• While astrocyte-derived signals for excitatory synapses are known, those regulating inhibitory synapse development remain largely unidentified.
• Understanding astrocyte signaling in inhibitory synapse formation is key to comprehending neural circuit development and function.

Approach:

• Utilized a combination of in vitro and in vivo experimental models.
• Employed super-resolution microscopy and in vivo proximity labeling (secreted TurboID) techniques.
• Generated Neurocan knockout mice to assess the protein's role in synapse development.

Key Points:

• Identified Neurocan, an astrocyte-secreted chondroitin sulfate proteoglycan, as a novel inducer of inhibitory synapse formation.
• Demonstrated that the C-terminal fragment of Neurocan, not the full protein, localizes to synapses and regulates inhibitory synapse development.
• Showcased Neurocan's specific localization to somatostatin-positive inhibitory synapses, highlighting its role in circuit-specific regulation.
• Neurocan knockout mice exhibited deficits in inhibitory synapse number and function.

Conclusions:

• Neurocan acts as a key astrocyte-derived signal that specifically promotes the formation and function of cortical inhibitory synapses.
• The distinct localization of Neurocan fragments after secretion is critical for its synaptogenic activity.
• This study elucidates a novel astrocyte-to-neuron communication pathway essential for inhibitory circuit development in the mammalian brain.