Astrocyte: Structure, Function and Disease

Astrocytes are star shaped glial cells which are found associated with the neurons of the CNS and spinal cord. 

• They modulate the aspects related to neural network functions.
• Express the same sets of ion channels as neurons, but in varying proportion.
• Maintenance of K+ and water homeostasis in the CNS via coordinated action of Kirl.4 and aquaporin 4 channels.
• Gap junctions form intercellular networks and help in sequestering K+ and glutamate.
• Modulation of synaptic transmission. 

1. Lamellar fibrous astrocytes

• Found in white matter
• Oriented parallel to the neuronal axons
• Higher levels of GFAP
• End feet envelops the node of Ranvier

2.  Smooth radial astrocytes

• Found in cerebellum equipped with a large repertoire of receptors  which helps in sensing the activity of synapses. 
• High densities of glutamate transporters. 
• Cell body spans both gray and white matter.

3.  Protoplasmic astrocytes

• Found in gray matter of CNS.
• At least one of their process is in contact with the blood vessels.
• Low input resistance.
• Very negative membrane potential.
• Prominent glutamate uptake.
• Voltage and time independent K currents.
• End feet envelops the synapses.

GFAP – Glial fibrillary acidic protein: biomarker of Astrocytes.

Plasma membrane ion channels

1. Cx43 channels

•  It’s selective for second messengers (cAMP, IP3 and calcium), amino acids (Glutamate, aspartate and taurine), Nucleotide (ADP, ATP, CTP and NAD), Energy metabolites (glucose, glucose 6 phosphate and lactate), small peptides (glutathione) and RNA (24 mer).

• Not permeable for large molecules such as nucleic acids, proteins and lipids.

2. Cx30 channels

S.No	Receptors	Transporters
1	Purine receptors	Glutamate transporter
2	mGlu receptors	Glucose transporter

Uptake of glutamate by glial specific transporters:

EAAT1 (Excitatory amino acid transporters) (in rodent it’s known as GLAST (glutamate aspartate transporter) and GLT1 (glutamate transporter 1)) and EAAT2. 

Function of Astrocytes:

(1) Astrocyte functions include modulation of synaptic function via glutamate transporters, which convey glutamate from the synaptic cleft into the cell.

(2) Communication between astrocytes occurs via ATP release and binding to purine receptors on adjacent astrocytes. ATP binding results in phospholipase C activation, with subsequent downstream activation of inositol trisphosphate, resulting in calcium mobilization.

(3) Gap junctions contribute to an astrocyte syncytium for the exchange of small molecules and cell–cell communication.

(4) Metabolic functions include

• The replenishment of neuronal glutamate via the glutamate glutamine cycle. (4)
• The transport of glucose from the vasculature. (5)

(6) The regulation of blood flow is modulated by astrocyte end-feet apposing blood vessels, with vasodilation being mediated through release of vasoactive substances.

(7) Glutamate release might occur following elevations in intracellular calcium and the activation of other factors related to prostaglandins.

(8) Glutamate release through hemichannels can be induced in vitro through lowering of extracellular calcium.

(9) Glutamate binding to metabotropic glutamate receptors activates intracellular calcium, leading to the release of vasodilatory substances. Abbreviations: Gln, glutamine; Glu, glutamate; IP3, inositol trisphosphate; PLC, phospholipase C.

Extra points:

Glutamate released from neurons increases glucose trafficking in Astroglial networks by activating AMPA (a-amino-3-hydroxy-5-methyl-4-Isoxazole propionic acid) receptors.

Homotypic Cx30 and Cx43 channels and heterotypic Cx43 – Cx30 channels are voltage dependent.

Astroglial networks supply glucose and lactate to sustain hippocampal synaptic transmission and studies investigating the role of IP3 in hippocampal function suggested that this molecule can induce glutamate release from gap junction coupled astrocytes, triggering transient depolarization and epileptiform discharges in CA1 Pyramidal neurons. 

Function related to neural formation:

Control of synapse formation and function

Regulating number, size and shape of dendritic spines in Hippocampal CA1 pyramidal neurons via EphA3-A4 receptors.

Adult neurogenesis

Instructing neuronal fate commitment and by promoting proliferation of adult neural stem cells. Moreover the effects of astrocytes are regionally specified: astrocytes from adult hippocampus retain the potential to promote neurogenesis, but astrocytes from adult spinal cord do not.

Astrocyte excitation happens in two main forms:

Generated by chemical signals in neuronal circuits(Neuron dependent excitation).

Occurs independently of neuronal input (spontaneous excitation).

Propagation of glutamatergic transmission via the astrocyte network.

Propagation of glutamate transmission through the astrocyte syncytium occurs through two prominent calcium-mediated mechanisms:

• Gap junctions
• Paracrine release of ATP

Activation of metabotropic glutamate receptors on astrocytes following neuronal release of glutamate results in the activation of an inositol trisphosphate (IP3) pathway, which induces calcium release from intracellular stores. This calcium can then be transferred to the adjacent astrocyte through connexin 43 (Cx43) gap junctions, thereby producing a calcium wave through an astrocyte syncytium. IP3 also activates ATP release through Cx43 hemichannels. This ATP release acts in a paracrine fashion, activating purine receptors on adjacent astrocytes. This activation results in IP3 production, more ATP release and intracellular calcium mobilization through a feed-forward mechanism.

Astrocytes association with Neurodegenerative Disease

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