Astrocyte-secreted neurocan controls inhibitory synapse formation and function.

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• Astrocytes secrete proteins that influence synapse development.
• While proteins promoting excitatory synapse formation are known, those for inhibitory synapses are less understood.

Purpose of the Study:

• To identify astrocyte-secreted proteins that regulate inhibitory synaptogenesis.
• To elucidate the role of neurocan in inhibitory synapse formation and function.

Main Methods:

• Identification of neurocan as an astrocyte-secreted synaptogenic protein.
• Analysis of neurocan fragments and their localization using super-resolution microscopy.
• In vivo proximity labeling with secreted TurboID.
• Astrocyte-specific rescue experiments in neurocan knockout mice.

Main Results:

• Neurocan is secreted by astrocytes and cleaved into distinct N- and C-terminal fragments.
• The C-terminal fragment of neurocan localizes to synapses and is essential for inhibitory synapse formation and function.
• Neurocan knockout mice exhibit deficits in inhibitory synapse number and function.
• The synaptogenic domain of neurocan specifically targets somatostatin-positive inhibitory synapses.

Conclusions:

• Neurocan is an astrocyte-derived factor that promotes inhibitory synaptogenesis.
• The C-terminal fragment of neurocan plays a critical role in regulating the development and function of cortical inhibitory circuits.
• This study reveals a novel mechanism for astrocyte-mediated control of circuit-specific inhibitory synapse development in the brain.