Morphological correlates of pyramidal cell axonal myelination in mouse and human neocortex.

The axons of neocortical pyramidal neurons are frequently myelinated. Heterogeneity in the topography of axonal myelination in the cerebral cortex has been attributed to a combination of electrophysiological activity, axonal morphology, and neuronal-glial interactions. Previously, we showed that axonal segment length and caliber are critical local determinants of fast-spiking interneuron myelination. However, the factors that determine the myelination of individual axonal segments along neocortical pyramidal neurons remain largely unexplored. Here, we used structured illumination microscopy to examine the extent to which axonal morphology is predictive of the topography of myelination along neocortical pyramidal neurons. We identified critical thresholds for axonal caliber and interbranch distance that are necessary, but not sufficient, for myelination of pyramidal cell axons in mouse primary somatosensory cortex (S1). Specifically, we found that pyramidal neuron axonal segments with a caliber < 0.24 µm or interbranch distance < 18.10 µm are rarely myelinated. Moreover, we further confirmed that these findings in mice are similar for human neocortical pyramidal cell myelination (caliber < 0.25 µm, interbranch distance < 19.00 µm), suggesting that this mechanism is evolutionarily conserved. Taken together, our findings suggest that axonal morphology is a critical correlate of the topography and cell-type specificity of neocortical myelination.

Myelination synchronizes cortical oscillations by consolidating parvalbumin-mediated phasic inhibition.

Parvalbumin-positive (PV+) γ-aminobutyric acid (GABA) interneurons are critically involved in producing rapid network oscillations and cortical microcircuit computations, but the significance of PV+ axon myelination to the temporal features of inhibition remains elusive. Here, using toxic and genetic mouse models of demyelination and dysmyelination, respectively, we find that loss of compact myelin reduces PV+ interneuron presynaptic terminals and increases failures, and the weak phasic inhibition of pyramidal neurons abolishes optogenetically driven gamma oscillations in vivo. Strikingly, during behaviors of quiet wakefulness selectively theta rhythms are amplified and accompanied by highly synchronized interictal epileptic discharges. In support of a causal role of impaired PV-mediated inhibition, optogenetic activation of myelin-deficient PV+ interneurons attenuated the power of slow theta rhythms and limited interictal spike occurrence. Thus, myelination of PV axons is required to consolidate fast inhibition of pyramidal neurons and enable behavioral state-dependent modulation of local circuit synchronization.

The brain contains billions of neurons that connect with each other via cable-like structures called axons. Axons transmit electrical impulses and are often wrapped in a fatty substance called myelin. This insulation increases the speed of nerve impulses and reduces the energy lost over long distances. Loss or damage of the myelin layer ­ as is the case for multiple sclerosis, a chronic neuroinflammatory and neurodegenerative disease of the central nervous system ­ can cause serious disability. However, a fast-firing neuron within the brain, called PV⁺ interneuron, has short, sparsely myelinated axons. Even so, PV⁺ interneurons are powerful inhibitors that regulate important cognitive processes in gray matter areas, including the outermost parts, in the cortex. Yet it remains unclear how the unusual, patchy myelination affects their function. To examine these questions, Dubey et al. used genetically engineered mice either lacking or losing myelin and studied the impact on PV⁺ interneurons and slow brain waves. As mice progressively lost myelin, the speed of inhibitory signals from PV⁺ interneurons did not change but their signal strength decreased. As a result, the power of slow brain waves, no longer inhibited by PV⁺ interneurons, increased. These waves also triggered spikes of epileptic-like brain activity when the mice were inactive and quiet. Restoring the activity of myelin-deficient PV⁺ interneurons helped to reverse these deficits. This suggests that myelination, however patchy on PV⁺ interneurons, is required to reach their full inhibitory potential. Moreover, the findings shed light on how myelin loss might underpin aberrant brain activity, which have been observed in people with multiple sclerosis. More research could help determine whether these epilepsy-like spikes could be a biomarker of multiple sclerosis and/or a target for developing new therapeutic strategies to limit cognitive impairments.

Local axonal morphology guides the topography of interneuron myelination in mouse and human neocortex.

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.