Notes

Glial Cells - Astrocytes

Glial Cells

• Central Nervous System
  • Microglial cell
  • Astrocyte
  • Oligodendrocyte
• Peripheral Nervous System
  • Satellite cells
  • Schwann cells

Astrocyte There exist two different main morphologies of astrocytes in grey and white matter.

• Grey Matter Astrocytes (Protoplasmic) They have a spongy look and are difficult to represent. They touch on blood vessels as they have control over blood regulation.
• White Matter Astrocytes (Fibrous)

Astrocytes Form a Network Astrocytes form networks through gap junctions: gap junctions form a channel between 2 membrane, they allow ions and metabolites to pass between cells and are made of connexin (Cx) proteins. Astrocytes: Cx30 and Cx43. They form sort of synapses between each other in a network even though they are not excitable cells.

Rodent vs. Human Astrocytes

• Structural Complexity: human astrocytes are bigger than rodents ones and the number of the main processes is way bigger in humans.
• Domains are way bigger in humans.
• Mice Implanted with Human Astrocytes: about 10 years ago, human astrocytes were implanted into mice's and they found that LTP was enhanced.
  • Neurons displayed enhanced long-term potentiation (LTP).
  • Animals learned faster.

Astrocyte Structure

• The Astrocyte connects three parts in the Neurovascular Unit: Neurons, Astrocytes and Blood Vessels.
• Tripartite Synapse: Astrocytes surround synapses. Glia transmission, they are releasing neurotransmitters in the synaptic cleft.

They release transmitters and influence synapses thorough a morphological change in synapse coverage. It is a really plastic system with a lot of different spatial and temporal scales of how astrocytes modulate synaptic strength.

Astrocyte Calcium Signaling When a neuron spikes there is a concurrent increase in calcium concentration. Calcium concentrations in astrocytes is mirroring neuronal activation. Two pathways:

• Direct calcium influx through ion channels.
• Release from the ER via GPCR and second messengers ($IP_3$). The cell shows local domain increases due to its complex morphology, i.e., there are many subdomains. Calcium waves between astrocytes has also been reported:
• Gap junctions.

Long-Term Two-Photon Imaging of Identical Cell Populations Mice cortex has been exposed, genetically encoded viruses are injected to visual calcium concentrations with two-photon imaging. Through whisker stimulation neurons shows spiking activity, sorting these neuronal traces by time they show to be pretty fast. On the contrary, astrocytes respond much slower to the whisker stimulation. However, there are neuronal subdomains that listen to the neuron activation. The correlation in time between the neuron and the astrocytes surrounding it, they show that the activation of the neuron likely elicits the activation of surrounding astrocytes.

Functional Roles of Astrocytes

• Energy Metabolism
• Neurotransmission
• Biosynthesis
• Waste Recycling
• Local Blood Flow Regulation

Energy Metabolism in the Brain

Energy Metabolism Astrocytes are very nicely located to take up blood vessels energy substrates. They do so through GLUT1, which brings glucose into the astrocytes. Then, a cascade of metabolic processes takes place which brings to the formation of Lactate. The Lactate is then shuttled to neurons. We have to realize that glucose can also directly be delivered to neurons without the need of astrocytes to process it. Oxygen is passively diffused (it is not an active transport) through the entire tissue, with a high oxygen pressure in the vessel. All of the Lactate transport follows the chemical gradient, which implies that the astrocytes have an higher concentration of Lactate than neurons, which allows the flow.

Neurotransmission Glutamate released from the neuron is taken up by astrocytes. If this process fails, a lack of astrocytic uptake of Glutamate leads to hyperexcitability. Also, GABA is mostly taken up by astrocytes.

• Glutamate-Glutamine Shuttle
  • Synaptic glutamate is taken up through excitatory amino acid transporters (EAATs).
  • Astrocytes either convert it to glutamine (via glutamine synthase, only present in the astrocytes) or intermediates of the TCA cycle.
  • Glutamine is transported back to neurons.
• GABA
  • GABA is taken up through GABA transporters (GATs).
  • It enters the TCA cycle.

Biosynthesis The nervous system always needs to form a lot of new stuff, which are provided in a large extent from astrocytic metabolism. In neurons, this is mainly done through Glutamate uptake.

• Glucose: diverted through the astrocytic PPP generates NADPH and precursors for the synthesis of nucleotides and amino acids.
• Pyruvate: carboxylated into the Krebs cycle intermediate oxalo-acetate (OAA), which is a precursor of multiple biosynthetic pathways in astrocytes and, through shuttling of glutamine, is also the main precursor for neuronal biosynthesis.

Waste Recycling Astrocytic waste recycling is extremely important, tons of stuff happening to make sure that the neuron well-being is maintained. Astrocytes buffer potassium (very important), to avoid that there are excessive potassium ions which need to be cleared. K+ ATPase pumps potassium ions into astrocytes. Another major thing is the scavenge reactive oxygen species produced in many processes in the neuron happens through astrocytes.

• Reactive Oxygen Species (ROS) in neurons are scavenged by ascorbate (AA) with the production of dehydroascorbic acid (DHA), which diffuses through the glucose transporters toward astrocytes to be recycled into AA, and is returned to neurons via anion channels and the SVCT2. Glutathione (GSH) reacts with ROS to generate glutathione disulfide (GSSG), or with xenobiotics to generate conjugated glutathione (GS-X), both of which are discarded via multidrug resistance proteins (MDR). GSH synthesized and released by astrocytes is cleaved in the interstice to cysteine, which controls the neuronal synthesis of GSH. Ammonia (NH3) released by the deamidation of glutamine into glutamate leaves neurons by an unknown pathway and is captured as ammonium (NH4), where it is recycled by glutamine synthase. K+ released by neurons during synaptic activity enters astrocytes via K+ channels and the Na+/K+ ATPase. Methylglyoxal is a side product of glycolysis, which is detoxified mostly in astrocytes by the glyoxalase system.

Glial Cells - Oligodendrocytes

Oligodendrocytes Oligodendrocytes are involved in the myelination of axons, which favors propagation speed and distance.

Myelin

• White matter tracts.
• Schwann cells in the PNS
• Oligodendrocytes in the CNS.

Oligodendrocyte Maturation and Myelin Formation

1. Infiltration of oligodendrocyte precursor cells (OPCs).
2. Formation of immature oligos.
3. Immature oligos send out processes to axons.
4. Signals induce wrapping of membrane.

Oligodendrocytes Can Respond to Neurotransmitters

• OPCs express neurotransmitter receptors.
  • Glutamate, GABA, Acetylcholine, Dopamine, ...
  • May influence migration and proliferation.
• Mature oligos express glutamate receptors.

Immature Oligos Choose Axons Based on Size and Attractive Signals They need to know what axons to wrap and that is probably done by attractive and repulsive signaling, which is probably performed by the neurons to attract or repel this oligos process.

Steps of Myelin Formation

Why Are Oligodendrocytes Important?

• Myelin formation is critical for increasing action potential mconduction.
• But Oligodendrocytes also:
  • Provide metabolic support to axons through myelin.
  • Affect signal processing and long distance communication by modulating the degree of axonal myelination.

Oligos Provide Metabolite to Axons

• Oligos and astrocytes are connected by gap junctions (Cx): allows the flow of metabolites.
• Oligos express MCT1 (lactate transporter): knockout of this transporter induces axonal degeneration.

Myelin "Plasticity"

• Oligo coverage changes throughout adult life based on experience and neuronal activity.
• Neuronal activity appears to induce OPC proliferation and maturation (i.e., MORE oligos).
• This process is necessary for learning new motor tasks.

Summary Oligodendrocytes

• Myelin Formation: OPCs infiltrate tissue and immature oligos wrap membrane around axons.
• Mature Myelin
  • Oligos provide metabolic support for axons.
  • The degree of myelination may regulate information processing.
• Myelin Plasticity
  • Changes throughout life.
  • Necessary for learning new motor tasks.

Glial Cells - Microglia

Microglia Microglia cells are involved in the "immune system" of the brain.

Three-Step Model of Microglial Phagocytosis Microglia need to react to different signals to find "disturbing" elements (e.g., apoptotic cells) and they do so by reacting to chemoattraction. Then, they receive signals to eat (phagocytose) these elements and digesting them.

Microglial Phagocytosis in Health Microglia are acting also when there is not necessary a lesion or something going "bad", but also during pruning. There is always microglial activity also when there is not some major problem going on.

Microglial Phagocytosis in Disease However, if there is something major going on, microglia play an important role in helping.

Cerebral Blood Vessels The brain is very densely vascularized, mainly because it has a very high energy consumption, which is associated with high oxygen requirements. Not all areas are equally vascularized. There exist three main types of vessels: arteriole, capillary and venule. It is important to notice that blood vessels don't allow the passage of any elements if not for gas diffusion (O2 and CO2) and those mediated by protein channels passages. Blood flow is often use to analyze the brain activity through fMRI as a non-invasive technique.