Distinctive Structural and Molecular Features of Myelinated Inhibitory Axons in Human Neocortex

Abstract

Numerous types of inhibitory neurons sculpt the performance of human neocortical circuits, with each type exhibiting a constellation of subcellular phenotypic features in support of its specialized functions. Axonal myelination has been absent among the characteristics used to distinguish inhibitory neuron types; in fact, very little is known about myelinated inhibitory axons in human neocortex. Here, using array tomography to analyze samples of neurosurgically excised human neocortex, we show that inhibitory myelinated axons originate predominantly from parvalbumin-containing interneurons. Compared to myelinated excitatory axons, they have higher neurofilament and lower microtubule content, shorter nodes of Ranvier, and more myelin basic protein in their myelin sheath. Furthermore, these inhibitory axons have more mitochondria, likely to sustain the high energy demands of parvalbumin interneurons, as well as more 2’,3’-cyclic nucleotide 3’-phosphodiesterase, a protein enriched in the myelin cytoplasmic channels that are thought to facilitate the delivery of nutrients from ensheathing oligodendrocytes. Our results demonstrate that myelinated axons of parvalbumin inhibitory interneurons exhibit distinctive features that may support the specialized functions of this neuron type in human neocortical circuits.

Significance Statement Numerous myelinated axons traverse the human neocortex, enabling fast and efficient signal transmission. Myelinated axons originate from both excitatory and inhibitory neurons, but their properties have rarely been studied in relation to parent neuron type. Here, we show that axons of inhibitory neurons have distinctive structural and molecular features that contrast with those of the majority of excitatory myelinated axons in human neocortex. These differences are likely to have important implications for neurological disorders that involve pathologies of myelinated axons. For example, the distinct molecular and structural organization of inhibitory and excitatory myelinated axons may underlie differences in their vulnerability in neurological disorders or to injuries, and may require different strategies for prevention and treatment.