A research team led by Joris de Wit at the VIB-KU Leuven Center for Brain & Disease Research has uncovered new molecular players critical for the formation and function of neuronal circuits in the brain. Through proteomic profiling of a specific synapse in the hippocampus, they identified multiple uncharacterized synaptic cell surface proteins, including a new regulator of connectivity. The insights help us understand how neuronal circuits orchestrate brain function in health and disease.
Neurons in our brain are dynamically connected with each other in complex circuits that process information. The specific patterns of connectivity within such circuits and at the sites of communication—the synapses—determine the circuit’s output, regulating anything from muscle activity to cognitive function.
To unravel the complex properties and plasticity of signal transmission, Nuno Apóstolo, PhD student in the lab of Joris de Wit at the VIB-KU Leuven Center for Brain & Disease Research, studied a central synapse in the hippocampus, a brain area important for memory.
“We isolated synapses of the hippocampal mossy fibers, a central type of synapse that integrates information from different types of neurons and is critical for hippocampal function,” explains Apóstolo. “In close collaboration with the lab of Jeffrey Savas at Northwestern University, Chicago, USA, we analyzed all of the proteins present at the cell surface and identified a diverse range of proteins, many of which were unknown to play a role at this—or even any—synapse.”
One such cell surface protein was the previously uncharacterized neuronal receptor IgSF8. The team’s experiments uncovered its role as a critical regulator of the connectivity and function of the mossy fiber microcircuit.
The findings are an important key to understanding brain function in health and disease, says Joris de Wit: “Although our study focused on the cell-surface proteins of one particular type of synapse, our dataset sheds new light on general mechanisms of synaptic function. Ultimately, we will need a combination of approaches like ours to elucidate the molecular mechanisms underlying the highly precise patterns of connectivity of the circuits in our brain.”
Synapse type-specific proteomic dissection identifies IgSF8 as a hippocampal CA3 microcircuit organizer, Apóstolo et al. Nat Comms 2020
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