Astrocyte Marker Proteins

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 Astrocyte Marker Proteins Background

The term “astrocyte” alludes to these cells’ star shaped morphology but does not characterize the heterogeneity or functions of this cell population. Generally, astrocytes function as structural support for neurons and neuronal synapses, formation and maintenance of ionic gradients, transmitter synthesis and removal, glutamate-glutamine metabolic cycling, glycogen storage, and maintenance of extracellular pH.

The term “astrocyte” (literally “star cell”) was first introduced in 1893 to describe the spindly cell shape. Like neurons and oligodendrocytes, astrocytes originate from the ectoderm. Contrary to long-held notions that astrocytes arise from homogeneous precursors, recent studies have discovered that astrocytes initially arise from specific sets of precursors that are non-overlapping and produce distinct astrocyte populations (in spinal chord, in brain). Astrocytes develop in concert with neurons, deriving information from neuronal signals and actively participating in synaptogenesis and synapse elimination.

Astrocytes are estimated to be the most abundant glial cell in the brain and can be categorized into subpopulations based on their morphology and location in the brain. Mature astrocytes have been classically categorized into two types based on morphology, fibrous astrocytes and protoplasmic astrocytes. Compared with protoplasmic astrocytes, fibrous astrocytes display fewer processes that are longer but less complex (i.e. branched less frequently and branch at more acute angles). Fibrous astrocytes occur mainly in the white matter of the brain and spinal cord and are arranged in an overlapping lattice structure. Protoplasmic astrocytes that are typically found in gray matter demonstrate non-overlapping arrangements where each astrocyte appears to occupy a unique domain, an anatomy referred to as “tiling”. Astrocytes are also proliferative and can generate additional astrocytes; indeed, recent studies indicate that astrocytes actively turn over in the brain throughout life, suggesting cell cycle regulation in astrocytes continues to be important beyond development. Adult astrocytes appear to functionally vary by brain region. For example, astrocytes in the brain stem are more sensitive to extracellular pH changes compared to astrocytes in the cerebral cortex, while astrocytes in the hippocampus are more vulnerable to apoptosis from lack of oxygen and glucose compared to astrocytes in the cortex.

Evidence across species points to increasing importance of astrocytes for cognitive function. For example, higher order species have an increased number of astrocytes compared with lower order species; humans have the highest astrocyte:neuron ratio of all. There is also increasing structural complexity of astrocytes; primates have larger astrocytes with more complex processes compared with rodents. Human astrocytes are also known to have enhanced functionality compared with astrocytes in other animals; for example, human astrocytes propagate calcium signals significantly faster than rodent astrocytes. Remarkably, recent data demonstrates that cross-species transplantation of human astrocytes derived from stem cells results in enhanced memory task performance in recipient mice. Given the possible influence of astrocytes based on their morphology and their increased numbers in the brain across species, understanding astrocyte functions and the molecular mechanisms that regulate them may give insight into both health and disease states of the human brain.

What do astrocytes do? In a word, astrocytes are multifunctional; several areas are worth highlighting in forming a conceptual foundation of astrocyte function: (1) neurotransmission regulation, (2) electrical coupling and gap junctions, (3) gliotransmission, (4) metabolism and the blood brain barrier (5) astrogliosis and immune function. These functions are summarized in the diagram below and further described in the subsequent text.

Overview of astrocyte functionality

Figure 1 Overview of astrocyte functionality (Maragakis and Rothstein, 2006).

Astrocytes contribute to neurotransmission by clearing glutamate and other neurotransmitters from the synapse. Astrocytes account for >90% of the glutamate removal from the synaptic cleft. The two main glutamate transporters expressed in astrocytes are GLT-1 (i.e. EAAT2, Slc1a2) and GLAST (i.e. EAAT1, Slc1a3); these transporters also have distinct neuroanatomical expression patterns, with GLAST robustly expressed in the cerebellum and olfactory system while GLT-1 is more ubiquitously expressed throughout the brain. Once glutamate is taken up from the synapse, astrocytes can convert glutamate to glutamine via glutamine synthetase, an enzyme uniquely expressed in astrocytes in the brain. This conversion relies on a nitrogen source (e.g. ammonia) from the blood supply. The non-neuroactive glutamine is then released by System N transporters on astrocytes and taken up by System A transporters on neurons. These relationships allow for high fidelity of excitatory neurotransmission and an exchange of nitrogen metabolites between neurons and astrocytes.

Astrocytes also actively respond to both excitatory and inhibitory neurotransmitters. In response to glutamatergic neurotransmission, glutamate receptors at the astrocyte cell membrane (e.g. mGluR5) respond to neuronal activity with an elevation of their internal Ca2+ concentration. Increases in astrocyte Ca2+ concentrations trigger the release of compounds (e.g. ATP/adenosine) from glia that in turn induce feedback regulation of neuronal activity and synaptic strength. Although wellcharacterized in the literature, this mechanism remains somewhat controversial; recent results indicate that the expression of glutamate receptors responsible for this phenomenon in astrocytes (mGluR5) changes as a function of development and may not extend to adult tissues (e.g. mGluR5 expressed in young mice but minimal expression in adult mice. Astrocyte calcium signaling can also stimulate presynaptic intake of extracellular K+, resulting in neuronal hyperpolarization that can rapidly modulate neuronal network activity. Astrocytes also express GABA transporters and can affect inhibitory neurotransmission as well, although the specific mechanisms are not as well characterized due in part to the expression of identical GABA transporters on both neurons and glial cells. One study has reported a differential inhibition by GABA antagonists on glial GABA transporters versus neuronal GABA transporters; the physiological relevance of this finding and the exact roles of astrocytes in inhibitory neurotransmission remain to be investigated.

In general, astrocytes express many of the same types of neurotransmitter receptors as neurons, making them responsive to signals via glutamate, adenosine, ATP, GABA, histamine, norepinephrine, and acetylcholine. This responsiveness and active involvement in neurotransmission has elevated the astrocyte in theoretical discussions of the synapse and given rise to the term “tripartite synapse”. Given these diverse and numerous roles of astrocytes, stimuli that alter the function of astrocytes could thus also affect neurotransmission.