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.