Oligodendrocyte-specific<i>fus</i>depletion preserves CA1 single-unit fidelity and stabilizes network dynamics during chronic recording.

Abstract

<i>Objective.</i>Loss of oligodendrocytes (OLs) and myelin impairs neuronal firing and network stability, whereas enhancing oligodendrogenesis with clemastine improves electrophysiological stability in cortex and, to a lesser extent, hippocampus. Conditional depletion of<i>Fus</i>in OLs (<i>Fus</i>^OLcKO) drives developmentally regulated increases in myelin thickness via enhanced cholesterol biosynthesis. Here, we investigated whether<i>Fus</i>-depleted OLs differentially affected long-term extracellular recordings across cortical layers and hippocampal CA1.<i>Approach.</i>We performed chronic electrophysiological recordings in visual cortex and CA1 of<i>Fus</i>^OLcKO mice and littermate controls over 16 weeks, combined with endpoint histology.<i>Main results.</i>In<i>Fus</i>^OLcKO mice, visually-evoked single-unit detectability and firing rate in CA1 increased relative to wild-type littermates, whereas cortical recordings showed no improvement. At the population level,<i>Fus</i>^OLcKO cortex exhibited reduced firing rates and lower functional connectivity, indicating altered network dynamics. Post-mortem analysis revealed higher neuron density in recorded cortical regions acutely and greater excitatory synapse density in CA1 of<i>Fus</i>^OLcKO mice without significant changes in myelin profiles.<i>Significance. Fus</i>depletion in OLs enhances chronic hippocampal recordings but disrupts cortical network communication. These region-dependent effects highlight a differential role of OLs in supporting single-cell reliability versus population-level dynamics, offering novel insights into the interplay between oligodendrocytes, neural networks, and recording stability.