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Glia 3 Astrocytes

Astrocytes: Development and Function

Introduction

  • Glia development has been previously covered.
  • Astrocytes will now be examined, focusing on their function in a normal brain and in disease situations.
  • The roles of astrocytes are multiple, and this lecture will focus on the most validated and relevant ones.

Astrocytes and Synaptic Activity Regulation

  • Astrocytes regulate synaptic activity and are part of the blood-brain barrier.
  • Radial glia are similar to astrocytes in lineage and markers.
  • Astrocytes (including radial glia) play a role in neurogenesis, gliogenesis, synaptogenesis, and synaptic maturation.
  • Astrocytes are the most abundant cell type in the brain and are essential for the microarchitecture of the brain.
  • They communicate through gap junctions, forming microdomains to monitor a large brain territory.
  • These domains include neurons, synapses, and blood vessels.

Tripartite Synapse

  • The classical definition of a synapse includes a presynaptic and a postsynaptic element, both neuronal.
  • However, for the majority of synapses, there is a third element: an astrocytic element.
  • Approximately 60% of excitatory synapses are surrounded by astroglial membranes.
  • 80% of the large perforated synapses are in rats by astrocytes, according to this model.
  • In the cerebellum, each Bergmann cell (astrocyte) interrupts approximately 2000 to 6000 synaptic contacts from Purkinje cells.
  • Astrocytes can integrate and modulate synaptic information.

Astrocytes as Excitable Cells

  • Astrocytes respond to synaptic activity, as visualized with calcium imaging.
  • They exhibit an intracellular molecular response to synaptic activity, reacting to both presynaptic and postsynaptic stimulation.
  • This is usually visualized with the release of calcium from intracellular reservoirs.
  • Communication is bidirectional: astrocytes receive information from neurons and send information back to modulate synaptic activity.
  • Astrocytes detect neurotransmitters and have their own glial transmitters to signal back to neurons or other astrocytes.
  • This modulates the excitability of neurons.
  • If an astrocyte responds to synaptic activity via an increase in calcium concentration, the calcium can propagate to neighboring astrocytes through gap junctions.
  • This allows astrocytes to modulate synaptic activity distal from the original synaptic event.

Molecular Mechanisms of Synaptic Modulation

  • Astrocytes facilitate the clearance of glutamate and recycle it into glutamine for neurons.
  • Glutamate is released into the synaptic cleft and needs to be removed and transformed into glutamine.
  • Astrocytes have glutamate receptors and dissociate glutamate into glutamine via glutamine synthase.
  • Glutamine is then released and recaptured by the presynaptic neuron.
  • Astrocytes interfere with glutamate signaling by removing glutamate from the cleft.
  • Recycling glutamine allows astrocytes to synchronize neurons.
  • Glutamine can travel through astrocytes via gap junctions, allowing astrocytes to release glutamine synchronously to multiple neurons.

Glial Transmitters: ATP

  • ATP is a glial transmitter that targets purinergic and adenosine receptors, which are on astrocyte and neuronal membranes.
  • ATP is primarily produced by astrocytes.
  • ATP can signal to neighboring astrocytes to drive further calcium release.
  • ATP can also signal directly to neurons to modulate the release of glutamate.
  • It can also modulate the insertion of AMPA receptors in the postsynaptic terminal.
  • The release of ATP from astrocytes is connected to calcium waves, likely related to SNARE proteins.

Selective Response to Neurotransmitters

  • Astrocytes can selectively respond to a given neurotransmitter, depending on its origin.
  • In the striatum or hippocampus, astrocytes respond to cholinergic activation but not glutamatergic activation, even though they have glutamate receptors.
  • When astrocytes respond to cholinergic activation, they produce more glutamine, allowing more glutamatergic signaling.
  • This can generate long-term potentiation independent of neuronal activity.
  • Astrocytes integrate and modulate information non-linearly, depending on specific thresholds of acetylcholine and glutamate.
  • They can increase calcium concentration in response to low frequencies of stimulation or depress calcium concentration in response to high frequencies of stimulation.

Importance of Context

  • Response of astrocytes can depend on the specific role of the synapse in memory tasks or other functions. A lack of response to glutamate might be part of the encoding or function of that synapse.
  • Astrocytes might recapture glutamate without driving calcium waves, performing their role without eliciting an easily measurable response.

Blood-Brain Barrier (BBB)

  • Definition and Importance:
    • The BBB is critical structurally and functionally, differing from other tissue barriers.
    • It's important for maintaining the brain's unique environment due to neuron sensitivity.
  • Peripheral Capillaries (Non-Brain):
    • Endothelial cells line capillaries with gaps called fenestrations (windows), allowing free flow of molecules.
  • Brain Capillaries:
    • Endothelial cells are closed by tight junctions, isolating the blood and parenchymal compartments.
    • The capillaries are completely wrapped by astrocyte foot processes creating another isolating layer.
    • Substances must pass through endothelial and astrocyte membranes to cross the barrier.
    • Requires flowing literally through the cells.
    • Blood needs to flow through two membranes of the endothelial cell and two membranes of the astrocyte.
  • Exceptions: Circumventricular Organs
    • The circumventricular organs (e.g., neurohypophysis, pineal gland) lack tight junctions and are involved in neuroendocrine signaling.
    • They allow quick access to blood for neurons that secrete hormones.
  • Selective Permeability Mechanism:
    • Molecules move via active transport
    • Specific transporters are used with associated energy requirements.
    • ABC transporters excrete antibiotics.
    • Amino acid and glucose transporters are required for neuronal function and energy supply.
    • Ion transporters are needed to maintain osmolarity.
    • Water channels (aquaporin-4, a marker of astrocytes) actively transport water into the brain.

Astrocytes in Disease: Traumatic Injuries (e.g., Spinal Cord Injury)

  • Traumatic injuries disrupt the BBB, leading to tissue disruption, activating astrocytes in a reactive way.
  • Anatomical Distribution in Spinal Cord Injuries:
    • In spinal cord injuries, long-distance axons are damaged.
    • Rupture of the BBB and tissue death occur, activating glial cells.
  • Astrocytes form a glial scar:
    • The glial cells proliferate near the injury site to limit damage by forming a barrier.
    • The astrocytes act to protect from injury caused by toxic molecules due to the break in the blood-brain-barrier.
  • Glial Scar Characteristics and Consequences:
    • The glial scar remains long-term, preventing axon regrowth.
    • It forms a physical and chemical barrier.
  • Axonal Regeneration and the Glial Scar:
    • Cross-sections of spinal cords show axonal damage and glial scar formation (identified by increased GFAP expression).
    • Axons attempting to approach the scar are rejected.
  • Cyst Formation and Molecular Barriers:
    • After debris clearance, a fluid-filled cyst forms, surrounded by the glial scar.
    • Axons not needing to cross the cyst and scar can regenerate, while those that do cannot.
    • Astrocytes express both growth-inhibiting and growth-promoting molecules.
  • Intrinsic Neuron Failure:
    • Studies suggest that the inability of neurons to cross the glial scar is due to intrinsic failure in the neuron to grow across this barrier.
  • Role of Pten
    • Pten inhibits the PI3K-Akt pathway, which is critical for axonal regeneration.
    • Inhibiting Pten in neurons promotes axon regrowth through glial scars.
    • The glial cells possess growth-promoting proteins regardless.
  • Positive vs. Negative Roles of Glial Scar:
    • The current understanding suggests that removing the glial scar is not necessary, as it has positive roles.
    • A combination of inhibiting negative aspects of glial cells and promoting axon growth is the best approach.

Conclusion

  • Astrocytes regulate synapses, contribute to the BBB, and are involved in traumatic injuries.
  • The next lecture will focus on another glial cell type.