A class-specific effect of dysmyelination on the excitability of hippocampal interneurons

Abstract

The role of myelination for axonal conduction is well-established in projection neurons but little is known about its significance in GABAergic interneurons. Myelination is discontinuous along interneuron axons and the mechanisms controlling myelin patterning and segregation of ion channels at the nodes of Ranvier have not been elucidated. Protein 4.1B is implicated in the organization of the nodes of Ranvier as a linker between paranodal and juxtaparanodal membrane proteins to the spectrin cytoskeleton. In the present study, 4.1B KO mice are used as a genetic model to analyze the functional role of myelin in Lhx6-positive parvalbumin (PV) and somatostatin (SST) neurons, two major classes of GABAergic neurons in the hippocampus. We show that 4.1B-deficiency induces disruption of juxtaparanodal K+ channel clustering and mislocalization of nodal or heminodal Na+ channels. Strikingly, 4.1B-deficiency causes loss of myelin in GABAergic axons in the hippocampus. In particular, stratum oriens SST cells display severe axonal dysmyelination and a reduced excitability. This reduced excitability is associated with a decrease in occurrence probability of small amplitude synaptic inhibitory events on pyramidal cells. In contrast, stratum pyramidale fast-spiking PV cells do not appear affected. In conclusion, our results indicate a class-specific effect of dysmyelination on the excitability of hippocampal interneurons associated with a functional alteration of inhibitory drive.

Functional myelin in cognition and neurodevelopmental disorders

“…Another compelling function of PV interneuron myelin sheaths is the clustering of mitochondria and thus the fine tuning of metabolic requirements during axonal activation [ 67 ]. Interestingly, other GABAergic neuron subtypes such as a fraction of somatostatin (SST)-expressing interneurons and, to a much lesser extent, vasoactive intestinal peptide (VIP)-expressing interneurons have myelin sheaths with layer-specific arrangements [ 63 , 68 , 69 ]. However, the functional and structural significance of this myelination, sometimes limited to a single internode per axon, remains largely unexplored, pointing to avenues for further investigation.…”

“…However, the functional and structural significance of this myelination, sometimes limited to a single internode per axon, remains largely unexplored, pointing to avenues for further investigation. Nevertheless, it has recently been reported that a myelin loss in SST interneurons in the hippocampus can be associated with a reduction in their firing frequency [ 69 ]. Finally, comparisons between seven different GABAergic and glutamatergic neurons show significant variations in their myelination patterns, with PV interneurons and thalamocortical axons exhibiting higher myelination probabilities [ 63 ].…”