Enhancing Oligodendrocyte Myelination Rescues Synaptic Loss and Improves Functional Recovery after Chronic Hypoxia

Abstract

To address the significance of enhancing myelination for functional recovery after white matter injury (WMI) in preterm infants, we characterized hypomyelination associated with chronic hypoxia and identified structural and functional deficits of excitatory cortical synapses with a prolonged motor deficit. We demonstrate that genetically delaying myelination phenocopies the synaptic and functional deficits observed in mice after hypoxia, suggesting that myelination may possibly facilitate excitatory presynaptic innervation. As a gain-of-function experiment, we specifically ablated the muscarinic receptor 1 (M1R), a negative regulator of oligodendrocyte differentiation in oligodendrocyte precursor cells. Genetically enhancing oligodendrocyte differentiation and myelination rescued the synaptic loss after chronic hypoxia and promoted functional recovery. As a proof of concept, drug-based myelination therapies also resulted in accelerated differentiation and myelination with functional recovery after chronic hypoxia. Together, our data indicate that myelination-enhancing strategies in preterm infants may represent a promising therapeutic approach for structural/functional recovery after hypoxic WMI.

Hepatic arginase deficiency fosters dysmyelination during postnatal CNS development

“…Furthermore, these findings implicate the function of oligodendrocytes, which appear to be significantly impaired in a deficiency of arginase 1. Interestingly, the density of myelinated axons in the spinal cord region is significantly higher than in the pyramidal tract, suggesting that CST axons are much more compact at the cervical spinal cord level; this localized area has been vigorously confirmed by many previous studies using different labeling techniques (29,30,33,37).…”

“…G-ratio analysis demonstrates increased ratio in the KO with recovery in AAV-treated mice. To quantitatively investigate myelination of CST axons in the pyramidal tract and spinal cord, and to further confirm the recovery of myelination after gene therapy at P2, at least 50 myelinated axons were randomly selected from each genotype for measuring the diameter of axon fibers and myelinated fibers; thus, the G-ratio was calculated for each axon (34)(35)(36)(37). For the first set of data ( Figure 6, A and B), we sought to reveal the relationship between G-ratio and myelinated axon diameter and to determine if there was a correlation in both pyramidal tract ( Figure 6A)…”

Preservation of a remote fear memory requires new myelin formation

“…Administration of clemastine to humans and rodents with inflammatory demyelination promotes remyelination and relieves the severity of clinical symptoms 35,36 . Clemastine additionally promotes myelination and rescues behavioral deficits in mice that are hypomyelinated following either prolonged social isolation or chronic hypoxia 36,37 . Nonetheless, clemastine-treated mice displayed persistent and high freezing responses over time, suggesting that increasing new myelin formation stabilizes remote fear memory ( Figure 5.1e).…”

Glial response to hypoxia in trachealess mutants induces synapse remodeling

“…After nerve injury, Schwann cells participate in synaptic homeostasis and remodeling during NMJ re-innervation [56]. Chronic hypoxia causes hypomyelination, leading to synaptic reduction in the mouse cortex, which could be rescued by genetically-induced or drug-enhanced hypermyelination [57]. In Drosophila , expansion of glial structures to synaptic boutons matches synaptic growth [44].…”