Myelination, the insulating ensheathment of axons by oligodendrocytes, is thought to both optimize signal propagation and provide metabolic support. Despite the well-established physiological importance of myelination to neuronal function, relatively little is known about the myelination of GABAergic interneurons in the cerebral cortex. Here, we report that a large fraction of myelin in mouse cerebral cortex ensheaths GABAergic interneurons, reaching up to 80% in hippocampal subregions. Moreover, we find that a very high proportion of neocortical and hippocampal parvalbumin (PV) interneurons exhibit axonal myelination. Using a combination of intracellular recordings and biocytin labeling of ex vivo human neocortex, we also confirm that axons of fast-spiking PV interneurons are extensively myelinated in the human brain. PV interneuron myelination in both mice and humans exhibits a stereotyped topography with a bias towards proximal axonal segments and relatively short internodes (~27 μm) interspersed with branch points. Interestingly, myelin-deficient Shiverer mice exhibit an increased density and more proximal location of en passant boutons, suggesting that myelination might function in part to regulate synapse formation along PV interneuron axons. Taken together, fast-spiking interneuron myelination is likely to have broad implications for cerebral cortex function in health and disease.

Axonal myelination of neocortical pyramidal neurons is modulated dynamically by neuronal activity. Recent studies have shown that a substantial proportion of neocortical myelin content is contributed by fast-spiking, parvalbumin (PV)-positive interneurons. However, it remains unknown whether the myelination of PV interneurons is also modulated by intrinsic activity. Here, we used cell-type-specific Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in adult mice to activate a sparse population of medial prefrontal cortex (mPFC) PV interneurons. Using single-cell axonal reconstructions, we found that DREADD-stimulated PV interneurons exhibited a nearly two-fold increase in total length of myelination, predominantly mediated by a parallel increase of axonal arborization and number of internodes. In contrast, the distribution of axonal interbranch segment distance and myelin internode length were not altered significantly. Topographical analysis revealed that myelination of DREADD-stimulated cells extended to higher axonal branch orders while retaining a similar interbranch distance threshold for myelination. Together, our results demonstrate that chemogenetically induced neuronal activity increases the myelination of neocortical PV interneurons mediated at least in part by an elaboration of their axonal morphology. Myelination is the wrapping of an axon to optimize conduction velocity in an energy-efficient manner. Previous studies have shown that myelination of neocortical pyramidal neurons is experience and activity dependent. We now show that activity-dependent myelin plasticity in the adult neocortex extends to parvalbumin (PV)-expressing fast-spiking interneurons. Chemogenetic stimulation of PV interneurons in the medial prefrontal cortex (mPFC) significantly enhanced axonal myelination, which was paralleled by an increase in axonal arborization. This suggests that activity-dependent axonal plasticity may involve changes in both structural morphology and myelination. Such multicomponent plasticity reveals an unexpected repertoire of anatomical parameters available for optimizing and adapting neuronal networks in response to experience.

GABAergic fast-spiking parvalbumin-positive (PV) interneurons are frequently myelinated in the cerebral cortex. However, the factors governing the topography of cortical interneuron myelination remain incompletely understood. Here, we report that segmental myelination along neocortical interneuron axons is strongly predicted by the joint combination of interbranch distance and local axon caliber. Enlargement of PV+ interneurons increased axonal myelination, while reduced cell size led to decreased myelination. Next, we considered regular-spiking SOM+ cells, which normally have relatively shorter interbranch distances and thinner axon diameters than PV+ cells, and are rarely myelinated. Consistent with the importance of axonal morphology for guiding interneuron myelination, enlargement of SOM+ cell size dramatically increased the frequency of myelinated axonal segments. Lastly, we confirm that these findings also extend to human neocortex by quantifying interneuron axonal myelination from ex vivo surgical tissue. Together, these findings establish a predictive model of neocortical GABAergic interneuron myelination determined by local axonal morphology.