Abstract
Multiple sclerosis (MS) has been clinically considered a chronic inflammatory disease of the white matter; however, in the last decade growing evidence supported an important role of gray matter pathology as a major contributor of MS-related disability and the involvement of synaptic structures assumed a key role in the pathophysiology of the disease. Synaptic contacts are considered central units in the information flow, involved in synaptic transmission and plasticity, critical processes for the shaping and functioning of brain networks. During the course of MS, the immune system and its diffusible mediators interact with synaptic structures leading to changes in their structure and function, influencing brain network dynamics. The purpose of this review is to provide an overview of the existing literature on synaptic involvement during experimental and human MS, in order to understand the mechanisms by which synaptic failure eventually leads to brain networks alterations and contributes to disabling MS symptoms and disease progression.
Highlights
Multiple sclerosis (MS) is a chronic, inflammatory and degenerative disease of the central nervous system (CNS), a leading cause of neurological disability in young adults and a central public health issue in the world-wide population [1,2]
The authors quantified the density of cortical fibers that mostly represent afferent intra- and extra-cortical axons, demonstrating a significant reduction of cortical axon density only in the demyelinated cortex [11]. These findings suggest that spine loss in the normal-appearing gray matter could represent a sign of primary synaptic damage in MS brains, not necessarily triggered by demyelination and/or axonal loss [11]
No correlation between cerebrospinal fluid (CSF) markers of axonal damage (i.e., neurofilament light chain (NfL)) and growth-associated protein 43 (GAP-43) has been found [91], suggesting that these two biomarkers reflect different pathophysiological mechanisms, with GAP-43 being characterized by a bidirectional behavior, where its CSF decrease may reflect a reduction in synaptogenesis potential and its CSF increase an ongoing neuronal and synaptic injury
Summary
Multiple sclerosis (MS) is a chronic, inflammatory and degenerative disease of the central nervous system (CNS), a leading cause of neurological disability in young adults and a central public health issue in the world-wide population [1,2]. Synapses are fundamental functional entities, expressing shortand long-term plastic changes, able to ensure learning processes, context-dependent input integration, multi-modal information processing and the ability to record, store and retrieve memory traces in cortical and subcortical brain networks [26,27]. Their malfunction and loss might critically contribute to connection failure in the MS brain [11,20]. The aim of this review is to discuss recent findings on functional and structural synaptic involvement in both experimental and human MS to understand the different mechanisms by which synaptic failure might contribute to networks dysfunction, driving the onset and progression of MS-related disability
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