Neuronal Activity-Dependent Myelin Plasticity during Adulthood

Abstract

Purpose : Oligodendrocytes in the central nervous system (CNS) produce myelin, which is essential for ensuring fast signal transmission in neurons, providing synchronization of neuronal impulses, and maintaining axonal health. Unlike previously believed, increasing evidence show that myelin changes throughout life. Oligodendrocyte precursor cells differentiate into myelinating oligodendrocytes until old age. Several studies demonstrate that de novo myelination onto previously unmyelinated axons and myelin remodeling of existing sheaths’ length, thickness, and number occurs in many CNS regions. Both human and murine studies suggest that neuronal activity plays a role in de novomyelination and myelin remodeling, the two components of myelin plasticity. In light of this, we asked how neuronal activity regulates myelin plasticity, and whether bidirectional changes could occur.

Methods : Using designer receptor exclusively activated by designer drugs (DREADDs), we increased and decreased neuronal activity of retinal ganglion cells via the Gq (hM3Dq) and Gi (hM3Di) pathways to observe myelin plasticity in the optic nerve. Recent studies showed that the inert DREADD ligand clozapine N-oxide does not cross the blood brain barrier, and that its metabolite clozapine is responsible for DREADD activation in vivo. Since clozapine is an antipsychotic drug that affects multiple endogenous receptors at high concentration, we performed a dose-response curve to determine the optimal concentration for long-term neuronal activity change without affecting endogenous receptors. Using the PDGFRα-CreER^T2:Tau-mGFP and OPALIN-iCreER^T2:Tau-mGFP mouse lines, which label newly myelinating and currently existing OLs, we quantified how neuronal activity regulates de novo myelination and myelin remodeling during adulthood.

Results : We demonstrated that clozapine has greater affinity to DREADDs in vivo than CNO and at low concentrations, clozapine does not cause off-target effects. Moreover, we showed that neuronal activity bidirectionally affects the rate of differentiation of OPCs as well as the morphology of existing and newly myelinating oligodendrocytes.

Conclusions : Our data suggest that myelinating glia can detect functional activity in axons and respond with adaptive change. Additionally, these findings indicate that activity-dependent communication may stretch beyond synaptic transmission.

This is a 2021 ARVO Annual Meeting abstract.