Demyelination induces selective vulnerability of inhibitory networks in multiple sclerosis

Abstract

In multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system, neurodegeneration is detected early in the disease course and is associated with the long-term disability of patients. Neurodegeneration is linked to both inflammation and demyelination, but its exact cause remains unknown. This gap in knowledge contributes to the current lack of treatments for the neurodegenerative phase of MS. Here we ask if neurodegeneration in MS affects specific neuronal components and if it is the result of demyelination. Neuropathological examination of secondary progressive MS motor cortices revealed a selective vulnerability of inhibitory interneurons in MS. The generation of a rodent model of focal subpial cortical demyelination proved that this selective neurodegeneration is secondary to demyelination providing the first temporal evidence of demyelination-induced neurodegeneration and a new preclinical model for the study of neuroprotective treatments.

Neuron–Oligodendrocyte Communication in Myelination of Cortical GABAergic Cells

“…Pathological changes in this dynamic dialog between GABAergic neurons and oligodendrocyte lineage cells may contribute to some CNS psychiatric disorders [ 222 , 223 ]. Recent work on post-mortem tissue also suggests inhibitory cells of the motor cortex may be selectively vulnerable to secondary, progressive demyelinating diseases such as multiple sclerosis [ 224 ]. Dissecting mechanisms of bi-directional communication between oligodendroglia and their precursors and GABAergic cells will improve understanding of such vulnerabilities and help develop better therapies for neurological disorders.…”

Microglial Pruning: Relevance for Synaptic Dysfunction in Multiple Sclerosis and Related Experimental Models

“…Widespread structural loss of spines in non-affected cortical regions in MS [ 65 ], and similarly in EAE [ 63 , 66 ], appears as a primary event, occurring early in the course of the disease, independently of demyelination and axonal damage [ 2 , 3 , 65 , 67 , 68 , 69 ] ( Figure 2 ).…”

“…Multiple sclerosis (MS) is a demyelinating, inflammatory, immune-mediated central nervous system (CNS) pathology in which neuronal death has traditionally been considered the consequence of prolonged and severe axonal damage related to myelin loss. Nevertheless, primitive neurodegeneration independent of demyelination, involving different grey matter (GM) regions of the CNS [ 1 , 2 , 3 , 4 ], is emerging as an important contributor to patients’ long-term disability [ 1 , 5 , 6 ]. Primitive GM damage is believed to play a primary role in the pathogenesis of the complex behavioural, psychiatric and cognitive disturbances that, together with sensory-motor impairment, affect the employment potential, social activities and quality of life of MS patients [ 1 , 5 ].…”

Injectable Glycosaminoglycan-Based Cryogels from Well-Defined Microscale Templates for Local Growth Factor Delivery

“…Cryogels are typically quite robust, exhibiting good tough mechanical properties, making them easy to handle for applications in ex vivo slice culture 18 , 19 and local delivery. 20 However, in addition, their ability to be compressed through an injection cannula is of interest for use in the brain, 21 where surgical intervention is limited. Unlike spherical microscale cryogels (termed microcarriers) developed for cell culture 22 /cell transplantation, 11 this work aimed to produce high-aspect-ratio, fiber-like cryogels as a step toward bridging anatomically connected regions of the brain or nervous system.…”