What Makes Myelinated Axons of Human Inhibitory Neurons So Special?
This article was a highlight for me because Micheva and colleagues identified several structural and molecular features in human neocortex that distinguish myelinated axons that arise from inhibitory (GABAergic) neurons from those that arise from excitatory (non-GABAergic) neurons. Myelin is most known for its role in axon insulation to increase the speed at which action potentials are propagated to a distant post-synaptic cell. As excitatory neurons are the primary source of these long-distance axons, myelination is not typically associated with the axons that originate from inhibitory neurons. However, technological advances have enabled higher-level cellular reconstruction and immunolabeling processes that have revealed the presence of myelin on many short-axon inhibitory interneurons in the mouse and human cortex.
Use of the light microscopy-based array tomography (AT) method developed by Dr. Micheva together with Professor Stephen Smith (formerly at Stanford University School of Medicine, CA) enabled Micheva and colleagues to show previously that a large proportion of myelinated inhibitory axons in mouse cortex from parvalbumin-positive (PV+) basket cells. In their eNeuro publication, Micheva, now working in the laboratory of Professor Daniel Madison (Stanford University, CA), and colleagues examined samples of human temporal neocortex that were excised during surgical procedures that targeted deeper epileptic foci. Ribbons of serial ultrathin 70-nm sections were immunolabeled with antibodies that detect myelin, inhibitory neurons (GABA as a general inhibitory marker; PV as a subset-specific marker), and cytoskeletal or mitochondrial proteins. One major advantage of this AT method was that once images of the expression patterns of a particular combination of antibody markers had been captured, the antibodies were eluted, and the tissue was restained with a different combination of antibodies. Precise realignment of each tissue section for subsequent microscopic analyses was enabled by unique landmarks, such as the distribution of DAPI-stained nuclei. Neocortical tissue isolated from a non-epileptic individual showed similar patterns of marker expression.
Figure 1. Schematic illustration of the distinct structural and molecular features of GABAergic and non-GABAergic myelinated axons in human neocortex. (Visual abstract from Micheva et al., 2018.)
Figure 1 shows a schematic illustration of the unique structural and molecular characteristics of myelinated inhibitory axons. Compared to myelinated excitatory axons, myelinated inhibitory axons exhibit higher neurofilament but lower microtubule content, shorter nodes of Ranvier, higher myelin basic protein content in their myelin sheath, and an increased number of mitochondria.
Because inhibitory axons project only short distances, the role of myelination is less clear in these neurons, but Madison hypothesizes that because inhibitory interneurons play such a central role in modulating the activity of local neuronal circuits, that even small changes in conduction velocity might tweak the precise timing of electrical activity and rhythms of those circuits. Micheva and colleagues also hypothesize that myelination of these axons could serve as a means of local insulation to support the high metabolic needs of PV+ basket cells. In this light, Micheva and colleagues found that the myelin around inhibitory axons has high levels of 2’,3’-cyclic nucleotide 3’-phosphodiesterase (CNP) expression. CNP is thought to generate the cytoplasmic channels within myelin that facilitate the passage of nutrients from ensheathing oligodendrocytes to axons. This study is an important advance in the field as it raises such questions about the functional relevance of myelination of human myelinated inhibitory axons
Future studies aimed at extending these findings underway in the Madison laboratory include combining electrophysiological recordings of myelinated excitatory or inhibitory neurons in mouse cortex with post-hoc immunolabeling using the AT technique. In this manner, the physiological consequences of myelination can be correlated with neurochemical expression profiles in individual cells to further understand the functional role of myelination in a cell type-dependent context. In addition, this level of structure-function analysis could be extended to animal models of neurological disorders or human tissue isolated from neurological disease states.
Read the full article:
Distinctive Structural and Molecular Features of Myelinated Inhibitory Axons in Human Neocortex
Kristina D. Micheva, Edward F. Chang, Alissa L. Nana, William W. Seeley, Jonathan T. Ting, Charles Cobbs, Ed Lein, Stephen J Smith, Richard J. Weinberg and Daniel V. Madison