Human astrocytes in the diseased brain

Abstract

Astrocytes are key active elements of the brain that contribute to information processing. They not only provide neurons with metabolic and structural support, but also regulate neurogenesis and brain wiring. Furthermore, astrocytes modulate synaptic activity and plasticity in part by controlling the extracellular space volume, as well as ion and neurotransmitter homeostasis. These findings, together with the discovery that human astrocytes display contrasting characteristics with their rodent counterparts, point to a role for astrocytes in higher cognitive functions. Dysfunction of astrocytes can thereby induce major alterations in neuronal functions, contributing to the pathogenesis of several brain disorders. In this review we summarize the current knowledge on the structural and functional alterations occurring in astrocytes from the human brain in pathological conditions such as epilepsy, primary tumours, Alzheimer's disease, major depressive disorder and Down syndrome. Compelling evidence thus shows that dysregulations of astrocyte functions and interplay with neurons contribute to the development and progression of various neurological diseases. Targeting astrocytes is thus a promising alternative approach that could contribute to the development of novel and effective therapies to treat brain disorders.

Keywords: Astrocytes; Brain; Humans; Pathology.

Fig. 1

Astrogliosis in pathological human brain. Top, schematic representation of different gradation of astrogliosis depending on the gravity of the insult. Bottom, astrocyte morphology in normal tissue from a human autopsy specimen far from a lesion (left), and in presence of moderate (middle) and severe diffuse reactive astrogliosis (right). For each condition, a brightfield immunochemistry for GFAP counterstained with haematoxylin is shown on the left, and an enlarged view of the boxed areas on the right. Scale bars: left, 50 μm; right, 20 μm. [upper part modified from (Sofroniew, 2009); bottom part from (Sofroniew and Vinters, 2010)].

Fig. 2

Alterations of astrocytes in CNS disorders. (a) Schematic representation of astrocyte-mediated regulation of synaptic activity in the healthy brain. (b–f) Changes of astrocytic receptors, transporters, ion channels and intracellular proteins in epilepsy (b), brain tumours (c), Alzheimer’s disease (d), major depressive disorder (e) and Down syndrome (f). Increases of expression/levels are indicated in red, decreases in blue. [AQP4: aquaporin 4; Cav: voltage-gated Ca²⁺ channels; Cx43 and Cx30: connexins 43 and 30; GAT3: GABA transporter 3; GFAP: glial fibrillary acidic protein; GLAST and GLT1: glutamate transporters; Glu: glutamate; GS: glutamine synthetase; GJs: gap junctions; Kir4.1: inwardly-rectifying K⁺ channels; mGluR5: metabotropic glutamate receptor 5; Nav: voltage-gated Na⁺ channels; xCT: cysteine-glutamate system].