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.