Cortical projection neurons as a therapeutic target in multiple sclerosis.

INTRODUCTION Multiple sclerosis (MS) is a chronic inflammatory-demyelinating disease of the central nervous system associated with lesions of the cortical grey matter (GM) and subcortical white matter (WM). Recently, cortical lesions have become a major focus of research because cortical pathology and neuronal damage are critical determinants of irreversible clinical progression. Recent transcriptomic studies point towards cell-type specific changes in cortical neurons in MS with a selective vulnerability of excitatory projection neuron subtypes. AREAS COVERED We discuss the cortical mapping and the molecular properties of excitatory projection neurons and their role in MS lesion pathology while placing an emphasis on their subtype-specific transcriptomic changes and levels of vulnerability. We also examine the latest magnetic resonance imaging techniques to study cortical MS pathology as a key tool for monitoring disease progression and treatment efficacy. Finally, we consider possible therapeutic avenues and novel strategies to protect excitatory cortical projection neurons. Literature search methodology: PubMed articles from 2000-2020. EXPERT OPINION Excitatory cortical projection neurons are an emerging therapeutic target in the treatment of progressive MS. Understanding neuron subtype-specific molecular pathologies and their exact spatial mapping will help establish starting points for the development of novel cell-type specific therapies and biomarkers in MS.