Transient juvenile demyelination impairs maturation and function of parvalbumin-positive interneurons in the prefrontal cortex

Recent studies have highlighted axonal myelination as a common feature of parvalbumin-positive (PV) interneurons throughout the cerebral cortex. However, the precise function of PV interneuron myelination remains incompletely understood. In this study, we used the cuprizone model of demyelination in mice to investigate how PV interneuron myelination might influence their neuronal physiology. Specifically, we examined whether impairing myelination from postnatal day 21 onwards, during a critical neurodevelopmental period of the prefrontal cortex (PFC), can affect PV interneuron maturation and function. Using whole-cell patch-clamp recordings to examine intrinsic properties of PV interneurons in the PFC, we found that juvenile demyelination in mice induced robust alterations of PV interneuron firing patterns. Specifically, we observed that demyelination caused an impairment in the ability of PV interneurons to sustain high-frequency firing associated with a substantial decrease in Kv3-specific currents. We also found a significant impairment in PV interneuron autaptic self-inhibitory transmission, a feature implicated in temporal control of PV interneuron firing during cortical network activity. Following a remyelination period of 5 weeks, PV interneuron properties were only partially recovered, suggesting that transient juvenile demyelination leads to long-lasting impairments of PV interneuron function. In contrast, adult demyelination had no significant effects on PV interneuron firing properties. Together, our data uncovers a critical period for juvenile myelination as an important factor in PFC PV interneuron development and brain maturation.