Neuroglial Advances: New Roles for Established Players

Abstract

Neuroglial cells perform numerous physiological functions and contribute to the pathogenesis of all diseases of the nervous system. Neuroglial neuroprotection defines the resilience of the nervous tissue to exo- and endogenous pathological challenges, while neuroglial defence determines the progression and outcome of neurological disorders. IN this paper, we overview previously unknown but recently discovered roles of various types of neuroglial cells in diverse physiological and pathological processes. First, we describe the role of ependymal glia in the regulation of cerebrospinal fluid flow from the spinal cord to peripheral tissues through the spinal nerves. This newly discovered pathway provides a highway for the CNS-body volume transmission. Next, we present the mechanism by which astrocytes control migration and differentiation of oligodendrocyte precursor cells (OPCs). In pre- and early postnatal CNS, OPCs migrate using vasculature (which is yet free from glia limitans perivascularis) as a pathfinder. Newly forming astrocytic perivascular endfeet signal (through semaphorin-plexin cascade) to OPCs that detach from the vessels and start to differentiate into myelinating oligodendrocytes. We continue the astrocyte theme by demonstrating the neuroprotective role of APOE-laden astrocytic extracellular vesicles in neuromyelitis optica. Next, we explore the link between astrocytic morphology and stress-induced depression. We discuss the critical role of astrocytic ezrin, the cytosolic linker defining terminal astrocyte arborisation and resilience to stress: overexpression of ezrin in prefrontal cortical astrocytes makes mice resistant to stress, whereas ezrin knockdown increases animals vulnerability to stress. Subsequently, we highlight the pathophysiological role of oligodendroglial lineage in schizophrenia by describing novel hypertrophied OPCs in the post-mortem patient's tissue and in a mouse model with OPCs overexpressing alternative splice variant DISC1-Δ3. These DISC1-Δ3-OPCs demonstrated overactivated Wnt/β-catenin signalling pathway and were sufficient to trigger pathological behaviours. Finally, we deliberate on the pathological role of astrocytic and microglial connexin 43 hemichannels in Alzheimer's disease and present a new formula of Cx43 hemichannel inhibitor with increased blood-brain barrier penetration and brain retention.

Keywords: Alzheimer's disease; astrocyte; depression; ependymoglia; extracellular vesicles; microglia; neuromyelitis optica; oligodendrocyte precursor cells; schizophrenia.