Astrocytes differentially respond to inflammatory autoimmune insults and imbalances of neural activity

Abstract

BackgroundNeuronal activity intimately communicates with blood flow through the blood–brain barrier (BBB) in the central nervous system (CNS). Astrocyte endfeet cover more than 90% of brain capillaries and interact with synapses and nodes of Ranvier. The roles of astrocytes in neurovascular coupling in the CNS remain poorly understood.ResultsHere we show that astrocytes that are intrinsically different are activated by inflammatory autoimmune insults and alterations of neuronal activity. In the progression of experimental autoimmune encephalomyelitis (EAE), both fibrous and protoplasmic astrocytes were broadly and reversibly activated in the brain and spinal cord, indicated by marked upregulation of glial fibrillary acidic protein (GFAP) and other astrocytic proteins. In early and remitting EAE, upregulated GFAP and astrocytic endfoot water channel aquaporin 4 (AQP4) enclosed white matter lesions in spinal cord, whereas they markedly increased and formed bundles in exacerbated lesions in late EAE. In cerebellar cortex, upregulation of astrocytic proteins correlated with EAE severity. On the other hand, protoplasmic astrocytes were also markedly activated in the brains of ankyrin-G (AnkG) and Kv3.1 KO mice, where neuronal activities are altered. Massive astrocytes replaced degenerated Purkinje neurons in AnkG KO mice. In Kv3.1 KO mice, GFAP staining significantly increased in cerebellar cortex, where Kv3.1 is normally highly expressed, but displayed in a patchy pattern in parts of the hippocampus.ConclusionsThus, astrocytes can detect changes in both blood and neurons, which supports their central role in neurovascular coupling. These studies contribute to the development of new strategies of neuroprotection and repair for various diseases, through activity-dependent regulation of neurovascular coupling.

Multiple sclerosis-related white matter microstructural change alters the BOLD hemodynamic response

“…Structural and functional aberrations in astrocytes are found in animal models of MS and in MS patients. [28][29][30][31][32][33] Astrocytes play a central role in many contemporary models of functional hyperemia. [70][71][72][73][74] Such models suggest that astrocytes, in both white (via fibrous astrocytes) 75 and grey matter (via protoplasmic astrocytes), 76 facilitate neural-vascular communication.…”

“…astrocytes) which, many models of neural-vascular coupling suggest, produce functional hyperemia. [28][29][30][31][32][33] Further, MS also features brain-wide aberrations in cerebral blood flow. 31,32,34 We wondered if these pathological changes in brain microstructure and physiology might result in alterations to the BOLD signal.…”

Mesial temporal lobe epilepsy with psychiatric comorbidities: a place for differential neuroinflammatory interplay

“…Glial proteins, such as metallothionein I and II (MT-I/II), are able to quench free zinc and modulate glutamatergic neurotransmission [12], and aquaporin 4 (AQP4), found in astrocytic endfeets, is a regulator of water homeostasis that majorly controls edema formation and tissue excitability [13,14]. In schizophrenia, upregulation of MT-I/II and of astrocyte and microglia markers have been documented in several brain regions [15-17].…”

Regulation of neurovascular coupling in autoimmunity to water and ion channels

“…Confocal image stacks (40 µm in thickness) were collapsed into 2D images. These images are modified from our recent paper [159]. …”

“…Protoplasmic astrocytes are found in gray matter and their processes contact synapses and blood vessel capillaries. Fibrous astrocytes are located in white matter and their endfeet contact nodes of Ranvier and capillaries [17, 18]. Radial glial cells are a more specialized population of astroglia that have a radial morphology and are usually vimentin-positive [19].…”