November 2020

PROTEINS ON NEURON SURFACES PROVE PIVOTAL FOR COMMUNICATION

Featuring: Jeffrey Savas, PhD

A cell-surface protein is essential for proper microcircuit function in the brain, according to a study published in Nature Communications.

These microcircuits help maintain balance between excitatory and inhibitory signals, a mechanism that is believed to play a part in neurodevelopmental disorders such as autism. These findings shed light on the influence of cell-surface proteins, according to Jeffrey Savas, PhD, assistant professor in the Ken and Ruth Davee Department of Neurology Division of Behavioral Neurology and a co-corresponding author of the study.

“This research represents a first step towards elucidating the molecular mechanisms underlying the highly precise patterns of connectivity that are required for proper hippocampal circuit and ultimately brain function,” said Savas, who is also a professor of Medicine in the Division of Nephrology and Hypertension and of Pharmacology.

Excitatory and inhibitory neurons are connected to each other via microcircuits, specific arrangements of cells that are one of the most basic forms of organization in the brain. While neurons themselves are generating signals, these connectivity patterns are critical for proper brain function, helping to maintain a balance between excitatory and inhibitory output.

Cell surface proteins (CSPs) are an important piece of all intercellular communication. They have been known to play a role in microcircuit connectivity, but exactly how they work has remained unknown, according to Savas.

“Only recently have we started determining the CSPs expressed in discrete neurons that form extracellular protein-protein interactions and regulate circuit development and function,” Savas said.

Synapses in the hippocampal mossy fiber pathway are a part of microcircuits critical for hippocampal function. In the current study, investigators isolated pre- and post-synaptic membranes and used mass spectrometry to identify proteins on the surface of the cells.
Savas and his collaborators discovered adhesion proteins, extracellular matrix proteins and several previously unknown proteins. One protein, IgSF8, was especially numerous, suggesting it was particularly important, Savas said.

The scientists then created synapses lacking IgSF8, finding those experimental models had impaired synaptic architecture; many synaptic junctions were missing, impairing cell-cell communication. In addition, loss of IgSF8 cause reduced feed-forward inhibition — essentially, removing a check on excitatory impulses that results in an overall increase in the excitability of these neurons.

These results are some of the first insights into the landscape of CSPs in microcircuits, and demonstrate the importance of the cell surface in functional microcircuits. Dysfunctional microcircuits have been implicated in many autism-like disorders, and this study should help scientists in the quest to better identify the causes of disorders and develop therapies, Savas said.

“These findings are most relevant for our understanding of neurodevelopmental disorders such as autism,” Savas said.

This study was supported by the National Institutes of Health grant R01AG061787 and The Hartwell Foundation.

This article was originally published in the Feinberg School of Medicine News Center on November 16, 2020.

Jeffrey Savas, PhD, assistant professor in the Ken and Ruth Davee Department of Neurology Division of Behavioral Neurology, professor of Medicine in the Division of Nephrology and Hypertension, and of Pharmacology, was a co-author of the study published in Nature Communications.