Lecture 10 - Glial biology I: The mighty astrocytes Flashcards
What are the proposed functions of various glial cells?
Support neurons to maintain neurons’ proper function, such as supporting neurotransmission, maintaining ionic balance in the extracellular space, insulating axons to speed up electrical communications, CNS and PNS repair and regeneration.
Functions of Glial Cells
1. What is the involvement of radial glia in brain development?
Some glia give rise to neurons, and others guide neurons to their correct location in the nervous system — so they are essential for brain development. During embryonic development, a specialized type of glia called radial glia divide to form neural progenitor cells. Moreover, the long processes of radial glia span the cortex, providing tracks along which newly generated neurons migrate to reach their correct location. Once all neurons are in place, the processes of radial glia degenerate and they form cortical astrocytes. Besides guiding neurons to their correct location, glia provide a scaffold along which axons grow. They perform this pathfinding function through both attractive and repulsive interactions with receptors present on the axon.
Why are astrocytes the “supporting stars”?
Astrocytes comprise the largest class of glial cells in the mammalian CNS. They have key roles in maintaining the blood-brain barrier, regulating regional blood flow, providing trophic, antioxidant and metabolic support to neurons, neurotransmitter recycling, and regulating synaptogenesis and synaptic transmission.
Classification of astrocytes
What are the two types of astrocytes?
Protoplasmic astrocyte
Fibrous astrocyte
Astrocytes are morphologically heterogeneous.
What do protoplasmic astrocytes have a role in?
A protoplasmic astrocyte is shown in close connection with a neuron and a capillary in the grey matter, constituting the so-called ‘‘neurovascular unit’’ and highlighting the roles of astrocytes in developmental synaptogenesis and in modulating the BBB.
What is the role of fibrous astrocytes?
A fibrous astrocyte is shown in a white matter tract, where it may interact with oligodendrocytes to promote myelination.
Functions of glial cells
- How do astrocytes support neuronal function?
Potassium (K+) buffering
Neurotransmitter concentration
Receptor response
Energy
Neurotransmission
Functions of glial cells
- How do astrocytes support neuronal function via potassium (K+) buffering?
Potassium (K+) buffering: When neurons fire action potential, they release K+ ion into the extracellular space. Because astrocytes have high concentrations of K+ channels in their membranes, they can act as spatial buffers: they take up K+ at sites of neuronal activity, mainly synapses, and release it at distant contacts with blood vessels.
Functions of glial cells
- How do astrocytes support neuronal function via neurotransmitter concentration?
Neurotransmitter concentration: High-affinity transporters located in the astrocyte’s plasma membrane rapidly clear the neurotransmitter glutamate from the synaptic cleft. Interference with these uptake mechanisms results in the high concentrations of extracellular glutamate that can lead to the death of neurons, a process
termed excitotoxicity.
Functions of glial cells
- How do astrocytes support neuronal function via receptor response?
Receptor response: Some of the astrocytes express glutamate receptors (e.g., Bergmann glia in the cerebellum). The binding of these ligands to glial receptors increase the intracellular Ca2+, which triggers Ca2+ waves in adjacent astrocytes that are connected by gap junctions.
Functions of glial cells
- How do astrocytes support neuronal energy needs?
Energy: The main energy substrate of the brain is glucose (glc), which crosses the endothelium and enters astrocytes via the glucose transporter GLUT 1. Glucose is converted by glycolysis into pyruvate (pyr), which is oxidized to C02 by the mitochondrial Krebs cycle, producing NADH and then ATP. Pyruvate also generates lactate (lac), which is shuttled via monocarboxylate transporters MCT4 and MCT2 to be used as an energy substrate by neurons. Astrocytes store energy in the form of glycogen.
Functions of glial cells
- How do astrocytes support neurotransmission?
Neurotransmission: Glutamate and γ-aminobutyric acid (GABA) are captured by astrocytic excitatory amino acid transporters (EAAT) and GAT, respectively, converted into glutamine and shuttled back to neurons for recycling via multiple astrocytic and neuronal transporters.
How does glucose metabolism occur in astrocytes and neurons?
Glucose converted to glucose-6-p
Which becomes
a. Glycogen via glycogen synthase (typically astrocyte not neurons)
b. Glycolysis into pyruvate and enter TCA cycle to generate ATP, or convert into lactate via LDH
c. Pentose phosphate pathway - generate precursors to nucleotides and nucleic acids
How do we measure intracellular Ca2+?
Chemical encoded Ca2+ indicator - Fura-2 fluorescent dye (510 nm)
Genetically encoded Ca2+ indicators - Cameleon (535 nm), GCaMP (515 nm)
Astroglial intracellular Ca2+ can be measured by anchoring GCaMP3 to cellular membrane
Functions of Glial Cells
2. How do astrocytes support synaptic signaling
Current view
2. Synaptic function:
Glia induce synaptogenesis and neurogenesis
Glia influence synaptic structure and synapse elimination
Glia modulate synaptic transmission
Astrocytes are important for the development of synapses. They prepare the surface of the neuron for synapse formation and stabilize newly formed synapse. In pathological states, such as axonal damage, astrocytes and presynaptic terminal temporarily retract from the damaged postsynaptic cell bodies. Astrocytes release neurotrophic and gliotrophic factors that promote the development and survival of neurons and oligodendrocytes. Astrocytes also protect other cells from the oxidative stress. For example, the glutathione peroxidase in astrocytes detoxifies toxic oxygen free radicals released during hypoxia, inflammation, and neuronal degeneration.
