Btbd11 supports cell-type-specific synaptic function.

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Synaptic transmission and plasticity vary across brain cell types.
• Understanding cell-type-specific synaptic composition is key to deciphering circuit function.

Purpose of the Study:

• To investigate cell-type-specific specializations in glutamatergic synapse composition.
• To identify novel proteins involved in inhibitory interneuron function.

Main Methods:

• Identified Btbd11 as an inhibitory interneuron-specific protein enriched at synapses.
• Investigated Btbd11's interaction with postsynaptic density protein 95 (Psd-95) and its role in liquid-liquid phase separation.
• Utilized knockout models (in vitro and in vivo) to assess the impact of Btbd11 deletion on glutamatergic signaling, network activity, and behavior.

Main Results:

• Btbd11 is a conserved, synapse-enriched protein specific to inhibitory interneurons.
• Btbd11 interacts with Psd-95 and can undergo liquid-liquid phase separation, suggesting phase-separated postsynaptic densities in these neurons.
• Btbd11 knockout reduced glutamatergic signaling onto parvalbumin-positive interneurons, disrupted network activity, and altered exploratory behavior and anxiety levels in mice.

Conclusions:

• Btbd11 is a critical regulator of glutamatergic synapse function in inhibitory interneurons.
• Btbd11 plays a significant role in maintaining brain circuit homeostasis and normal animal behavior.
• These findings reveal a cell-type-specific mechanism with implications for understanding neurological disorders.