Evidence That ITPR2-Mediated Intracellular Calcium Release in Oligodendrocytes Regulates the Development of Carbonic Anhydrase II + Type I/II Oligodendrocytes and the Sizes of Myelin Fibers

Abstract

Myelination of neuronal axons in the central nervous system (CNS) by oligodendrocytes (OLs) enables rapid saltatory conductance and axonal integrity, which are crucial for normal brain functioning. Previous studies suggested that different subtypes of oligodendrocytes in the CNS form different types of myelin determined by the diameter of axons in the unit. However, the molecular mechanisms underlying the developmental association of different types of oligodendrocytes with different fiber sizes remain elusive. In the present study, we present the evidence that the intracellular Ca2+ release channel associated receptor (Itpr2) contributes to this developmental process. During early development, Itpr2 is selectively up-regulated in oligodendrocytes coinciding with the initiation of myelination. Functional analyses in both conventional and conditional Itpr2 mutant mice revealed that Itpr2 deficiency causes a developmental delay of OL differentiation, resulting in an increased percentage of CAII+ type I/II OLs which prefer to myelinate small-diameter axons in the CNS. The increased percentage of small caliber myelinated axons leads to an abnormal compound action potentials (CAP) in the optic nerves. Together, these findings revealed a previously unrecognized role for Itpr2-mediated calcium signaling in regulating the development of different types of oligodendrocytes.

Postnatal age-differential ASD-like transcriptomic, synaptic, and behavioral deficits in Myt1l-mutant mice

“…Zbtb20 regulates neuronal development, synaptic transmission and plasticity, memory, and emotion (Jones et al, 2018;Ripamonti et al, 2020). Itpr2 regulates somatic calcium signaling and adenosine triphosphate (ATP) release in astrocytes and astrocyte-dependent synapse elimination (Yang et al, 2016) and microglial calcium signaling and differentiation (Mei et al, 2021).…”

ITPR2 Mediated Calcium Homeostasis in Oligodendrocytes is Essential for Myelination and Involved in Depressive‐Like Behavior in Adolescent Mice

“…Mei and colleagues have revealed that Itpr2 deficiency may reduce the percentage of OLs that prefer to myelinate large‐diameter axons in the CNS. [ 33 ] In current study, we noticed that TUNEL assay did not reveal significant changes in apoptotic OLs from Itpr2 iKO mice and therefore ruled out the possible effect of Itpr2 deletion on reducing OLs numbers by cell death. However, EdU incorporation assay in OPC cultures showed an increased proportion of proliferating OPCs after Itpr2 ablation, consistent with the increased percentage of PDGFRα + or NG2 + OPCs in Itpr2 iKO mice brain.…”

Evidence That DDR1 Promotes Oligodendrocyte Differentiation during Development and Myelin Repair after Injury

“…Myelin plays a crucial role in the rapid and precise conduction of action potentials [ 1 , 2 , 3 , 4 ]. Increasing evidence has demonstrated that abnormal myelin development contributes to the disease pathogenesis including Alzheimer’s disease, major depression, and schizophrenia [ 5 , 6 , 7 ].…”