Cortical projection neurons as a therapeutic target in multiple sclerosis

ABSTRACT

Introduction

Multiple sclerosis (MS) is a chronic inflammatory-demyelinating disease of the central nervous system associated with lesions of the cortical gray matter and subcortical white matter. 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 toward 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.

KEYWORDS:

• Cortical projection neurons
• cortical pathology
• magnetic resonance imaging
• multiple sclerosis
• single-cell RNA-sequencing
• transcriptomics

Article highlights

• Cortical MS lesions consist of various types of excitatory and inhibitory neurons responding selectively to inflammatory and demyelinating changes.

• Excitatory pyramidal neurons in supragranular cortical layers II/III are important for intra- and intercortical projections and provide a basis for information integration from local and distant areas.

• Cortical MS lesions are linked to meningeal inflammation and neuron subtype-specific molecular changes related to glutamate excitotoxicity, ionic imbalance, and mitochondrial dysfunction.

• Cortical MS lesions can be visualized in patients with MS using specific MRI techniques like MP2RAGE and ultra-high field strength MRI.

• Selective molecular and cellular pathological changes enable classification of neurons into spatially restricted neuronal subtypes with various levels of vulnerability towards MS lesion pathology.

• Neuroprotection in MS could be reached by hampering glutamate excitotoxicity and modulation of ion channel function as well as by development of cell type-specific molecular therapies including gene editing.

This box summarizes key points contained in the article.

Declaration of interest

L Schirmer filed a patent for the detection of antibodies against KIR4.1 in a subpopulation of patients with multiple sclerosis (WO2015166057A1). L Schirmer has received travel support from Novartis and Sanofi Genzyme. A Gass has received honoraria for lecturing and financial support for research from Bayer Schering, Biogen, Merck, Novartis, TEVA Neurosciences and Roche. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by intramural funding provided by the Medical Faculty Mannheim of Heidelberg University (to M Engelhardt and L Schirmer) and research grants from the Hertie Foundation (medMS MyLab, P1180016, to L Schirmer) and the National Multiple Sclerosis Society (FG-1902-33617, to L Schirmer). H Kapell was supported by student fellowships from the Hertie Foundation (medMS doctoral program) and the German Academic Scholarship Foundation.