Synapse type-specific proteomic dissection identifies IgSF8 as a hippocampal CA3 microcircuit organizer

Area of Science:

• Neuroscience
• Synaptic Plasticity
• Molecular Biology

Background:

• The hippocampal CA3 microcircuit integrates excitatory and inhibitory inputs to generate neural output.
• The mossy fiber (MF) synapse is crucial for CA3 circuit function, mediating direct excitation and indirect feedforward inhibition.
• Understanding the cell-surface protein (CSP) composition of synapses is vital for identifying regulators of neuronal connectivity.

Purpose of the Study:

• To profile the cell-surface proteome of the hippocampal MF synapse.
• To identify novel regulators of MF synaptic connectivity and function.
• To investigate the role of identified proteins in CA3 microcircuit excitability.

Main Methods:

• Proteomic profiling of isolated MF synaptosomes.
• Cell-surface interactome screening.
• Genetic manipulation (presynaptic Igsf8 deletion) in mouse models.
• Electrophysiological recordings of CA3 pyramidal neuron activity.

Main Results:

• Proteomic analysis revealed a diverse CSP landscape at the MF synapse, including uncharacterized proteins.
• IgSF8 was identified as a neuronal receptor enriched in the MF pathway.
• Presynaptic Igsf8 deletion led to impaired MF synaptic architecture and reduced bouton filopodia density.
• Loss of IgSF8 disrupted excitation/inhibition balance and increased CA3 pyramidal neuron excitability.

Conclusions:

• IgSF8 is a critical regulator of CA3 microcircuit connectivity and function.
• The study provides insights into the cell-surface protein interactome of excitatory synapses.
• Targeting IgSF8 may offer therapeutic potential for neurological disorders characterized by altered circuit excitability.