1.3 Astrocytes

Astrocytes

Star-shaped glial cells in the CNS that support neurons survival by:

• Regulating the extracellular environment

• Supplying nutrients

• Maintaining the blood–brain barrier

• Repairing after injury

Astrocyte Developmental Roles

• Neurogenesis and gliogenesis (stem-like)

• Neuronal pathfinding (guiding axons)

• Synaptogenesis (formation, maturation, elimination)

Astrocyte-secreted factors for synapse formation

• Cholesterol

• Protocadherins

• Netrin

• Integrins

• Steroids

• Thrombospondin

Astrocyte-secreted factors for synapse maturation

• Cholesterol

• ApoE

• Neuregulin

• TNFα

• TGFβ1

Astrocyte-secreted factors for synapse elimination

• Draper

• EphrinA3

How does Thrombospondin effect synapses?

Cause formation of (structurally normal but) silent synapses

GFAP

Intermediate filament forming the astrocyte cytoskeleton; provides scaffolding and gives the brain its structure

Alexander Disease

GFAP mutation resulting in over-expression of GFAP and GFAP dysfunction → Disrupts the blood–brain barrier and reduces glutamate reuptake, increasing glutamate in the cytoplasm → glutamate toxicity, killing neurons

Gap Junctions

Specialised cell membrane structures that allow rapid and regulated exchange of:

• Ions

• Metabolites (e.g. glucose)

• Signaling molecules

between neighboring cells

Astrocyte syncytium

A continuous network of astrocyte connected via gap junctions

Evidence for Astrocytes' Structural Role

• Conditional astrocyte ablation (removal) causes loss of brain structure

• GFAP/vimentin knock-out causes structural abnormalities

Astrocytes End-Feet

Processes that ensheath blood vessels (and synapses)

Astrocytes roles at the Blood–Brain Barrier

• Induce tight junction formation in endothelial cells

• Regulate blood flow and microvascular permeability

• Control extracellular matrix

• Neurotransmitter transport and angiogenesis

Neurovascular Coupling

Where neuronal activity triggers localised increases in cerebral blood flow via astrocytes, ensuring delivery of oxygen and glucose to active brain regions.

Vasodilation pathway via Astrocytes in Neurovascular coupling

Astrocytes Ca²⁺ leads to arachidonic acid (AA), then COX, then prostaglandins (PG), causing vasodilation

Vasoconstriction pathway via Astrocytes in Neurovascular coupling

Via 20-HETE (2HETE)

Percentage of brain energy consumed by neurons

About 90%

Where is glycogen stored in the brain?

Localised in Astrocytes

Astrocytes-neuron lactate shuttle (ANLS)

Where glutamate uptake stimulates astrocyte glycogenolysis, leading to lactate release, which fuels neurons

How does poor Astrocyte Metabolism lead to Stroke?

Loss of blood/glucose causes astrocyte metabolism support to fail, so neurons die within minutes.

Astrocyte role in neurotransmitter uptake

Astrocytes clear neurotransmitters from synapses and recycle them to protect against neurotoxicity

Astrocyte Glutamate Transporters

• EAAT1 (GLAST)

• EAAT2 (GLT1)

About 80% of synaptic glutamate uptake is from astrocytes

Astrocyte GABA Transporters

• GAT1

• GAT3

Astrocyte Glycine Transporters

GlyT1

Other neurotransmitters Astrocyte take up

• Monoamines (DA, NE, 5HT)

• Taurine

Glutamate-Glutamine Shuttle

Astrocytes take up glutamate and convert it to glutamine (via glutamine synthetase); glutamine is released, taken up by the presynaptic neuron and converted back to glutamate.

Excitotoxicity

Where Ischemia (Restriction in blood supply) causes transporter failure, so glutamate accumulates and neurons die

How do Astrocytes stop Excitotoxicity?

Prevent neuronal hyperexcitability by taking up K⁺ (via Kir4.1) released during action potentials and redistribute it through gap junctions (spatial buffering).

How does poor Astrocyte K⁺ regulation cause Epilepsy?

Excess extracellular K⁺ causes uncontrolled neuronal firing

Astrocyte receptors types (region dependent)

• AMPAR and NMDAR (cortex, spinal cord)

• P2X/P2Y (ubiquitous)

• GABA receptors (GluR cells, cerebellum)

• mGluRs (cortex, cerebellum)

Are Astrocytes electrically excitable?

NO - They are excitable via Ca²⁺ signals (rather than action potentials)

Ionotropic receptors causing Astrocyte Ca²⁺ signals

• AMPA

• P2X

→ Ca²⁺ influx

Metabotropic receptors causing Astrocyte Ca²⁺ signals

• mGluR

• P2Y

causing IP₃ to trigger Ca²⁺ release from the ER

How do Astrocyte Ca²⁺ waves propagate?

Gap junction diffusion of IP₃, and ATP release that activates neighbouring Astrocytes, creating regenerative Ca²⁺ waves

Gliotransmission

Release of neurotransmitters by astrocytes

Gliotransmitters released by astrocytes

• ATP

• Glutamate

• D-serine

• Taurine

• Homocysteine

Non-vesicular Gliotransmitter release mechanisms

• Hemichannels

• Reversed uptake

• Swelling

• ROS

Vesicular Gliotransmitter Release Mechanisms

Ca²⁺-dependent Exocytosis (using a different Ca²⁺ source than neurons)

Functions of Gliotransmission

Activate neuronal receptors and modulate synaptic strength (LTP, LTD, surround inhibition)

Tripartite Synapse

Contains:

• Presynaptic Neuron

• Postsynaptic Neuron

• Astrocyte

Astrocyte sense synapse activity and release gliotransmitters to modulate Pre- and Postsynaptic neurons.

Astrocytes and Breathing

Hypercapnia (↑ CO₂ in blood) increases Astrocyte Ca²⁺, causing ATP release that stimulates respiratory centres and increases ventilation.

Reactive Astrogliosis

Astrocyte response to CNS damage, forming a barrier at the lesion site to limit tissue damage.

Moderate Astrogliosis is protective but Severe Astrogliosis leads to glial scar formation, which limits spread of damage but inhibits axon regeneration.

Inhibitors of axon regeneration from Reactive Astrocytes

• NgR complex

• EphA4

• Plexin B1

• TCSPGs

Therapeutic strategy for CNS injury involving astrocytes

Modulating astrocyte reactivity to allow regeneration

Lithium and Astrocytes

Directly alters astrocyte gene expression

Upregulation / Downregulation

An increase in the transcription and expression of a gene, resulting in greater production of its mRNA and protein.

A decrease in the transcription and expression of a gene, resulting in lower production of its mRNA and protein.

Genes Downregulated by Lithium in Astrocytes

• LOX

• Gas1

• Fstl1

Genes Upregulated by lithium in Astrocytes

• Cntf

• Klf4

• Per1

Other Astrocyte-modifying drugs identified

• Pioglitazone

• MG262

• Prostaglandin J2