Glia (Diego) Flashcards
`What is the average makeup of cells of all neural cells?
Neurones 10%
Glia 90%
CNS Glia Cells:
- 85-90% Macroglia (80% Astrocytes, 5% Ependymal, 5% Oligodendrocytes)
- 10-15% Microglia
PNS Glia Cells:
- Schwann Cells
What are the 4 main functions of glial cells?
- to surround neurons and provide physical support (hold them in place)
- to supply nutrients and oxygen to neurons
- to insulate one neuron from another and facilitate synaptic communication
- to destroy and remove cell debris and unwanted molecules
But they do many other important things, including:
- Important developmental roles
- Active participants in synaptic transmission
- Fundamental role in brain disease and degeneration
What do satellite cells do?
Surround neurone cell bodies in ganglia
Regulate 02, COz. nutrient, and neurotransmitter levels around neurones in ganglia
What do Schwann cells do?
Located in PNS
Surround axons in PNS
Are responsible for myelination of peripheral axons
Participate in repair process after injury
What do oligodendrocytes do ?
Located in CNS
Myelinate CNS axons
Provide structural framework
What do astrocytes do ?
Located in CNS
Maintain blood-brain barrier
Provide structural support
Regulate ion, nutrient, and dissolved gas concentrations
Absorb and recycle neurotransmitters
Form scar tissue after injury
What do Microglia do?
Located in CNS
Remove cell debris, wastes, and pathogens by phagocytosis
What do ependymal cells do?
Located in CNS
Line ventricles (brain) and central canal (spinal cord)
Assist in producing, circulating, and monitoring of cerebrospinal fluid
What are the main developmental layers?
Germ layers:
- Ectoderm
- Mesoderm
- Endoderm
Forebrain (Prosencephalon)
- Telencephalon
- Diencephalon
Midbrain (Mesencephalon
Hindbrain (Rhombencephalon)
- Metencephalon
- Myelencephalon
Brain development timeline
Neurogenesis begins at around 6 weeks post conception, and brain development ends at roughly 18-20 years during synaptic pruning
Vasculogenesis in the telencephalic wall: by 6 weeks of gestation (CS14)
Endothelial blood brain barrier formation coincides with 6 weeks of gestation (onset of vasculogenesis)
Blood-CSF barrier across choroid plexus, pia-arachnoid barrier and CSF-brain barrier all show tight junctions similar to adult forms from 7 weeks of gestation onwards
How does radial glia development occur and what are they?
- They differentiate from neural progenitors early in development, with somata in the ventricular zone and extending prolongations to the pia
- They can give rise to all cell lineages, contributing to populate the brain and providing a scaffold for neuronal migration
What is O2A?
- Key stage O2A progenitor that can give rise to astrocytes and oligodendrocytes
- Cells acquire identity as they migrate and colonise specific regions, defined by the factors the encounter
What are NG2 cells?
NG2 cells, also known as oligodendrocyte precursor cells (OPCs), are a type of glial cell found in the central nervous system
While their main fate is to become oligodendrocytes, NG2 cells have the potential under certain conditions to differentiate into astrocytes
Schwann cell differentiation
-Neural crest cells give rise to Schwann cell precursors, also give rise to peripheral sensory and autonomic neurones and satellite cells of the dorsal root ganglia.
-Immature Schwann cells differentiate into myelinating or non-myelinating depending on early association with large or small diameter axons, respectively
-Their de-differentiation is an important process during Wallerian degeneration
Astrocyte maturation
The stages of astrocyte lineage development are poorly defined, lacking stage-specific markers and clearly defined developmental endpoints
Astrocyte functional heterogeneity is starting to emerge, suggesting the number and role of subpopulations is yet to be defined
Shh is a key precursor needed to transition to their precursor stage
From the precursor stage, Notch signalling is required to transition into the fully mature astrocyte
The maturation of the astrocyte population is progressive and mostly postnatal, generating subpopulations expressing different markers GAP vs S100b and having different morphology (cortex VS hippocampus)
What are some macrophages subpopulations in the brain
Microglia - Considered to be the same as a macrophage
Meninges (blood brain barrier)
Dendritic cell
Choroid plexus macrophage (blood - CSF barrier)
Perivascular macropage (perivascular space_
What are the basic characteristics of microglia?
Ramified morphology, tiling the brain parenchyma in
a mosaic-like distribution
Biggest differences in morphology between grey (ramified and white (bipolar) matter
Variable densities in different regions, with each cell covering an average volume of 50000 km3
Equipped with a repertoire immune “sensors” and “reactants”, allowing rapid and plastic reactions to disruptions of the brain’s homeostasis
What are the main functions of microglia?
Surveillant Microglia:
- In a resting state but actively survey the CNS environment with their long, branching processes
- Monitor neuronal health, synaptic activity, and the presence of pathogens or debris
- Crucial for maintaining CNS homeostasis and quickly respond to changes or damage
Pruning Microglia:
- Involved in synaptic pruning, a critical process during CNS development and plasticity
- Help eliminate excess and weak synapses to refine neural connections and ensure efficient neural circuitry
Neuromodulatory Microglia:
- Release various cytokines, chemokines, and other factors that can modulate neuronal activity and synaptic transmission
- Neuromodulatory microglia can influence neural circuitry and behavior, playing roles in pain modulation, cognition, and other neural processes
Proliferating Microglia:
- In response to CNS injury or disease, microglia can enter a proliferative state
- Proliferating microglia increase in number to help manage and contain damage, clear debris, and release factors that promote repair and regeneration.
Phagocytic Microglia:
- Activated in response to injury, disease, or infection
- They engulf and digest cellular debris, dead neurons, and pathogens
Brief history of microglia
1880: NissI staining developed by Franz Nissi, allowing visualization of cells including microglia
Niss and Robertson first described microglial cells, showing that microglia are related to macrophages. Stäbchenzellen (rod cells)
The activation of microglia and formation of ramified microglial clusters was first noted by Victor Babes while studying a rabies case in 1897
Babes noted the cells were found in a variety of viral brain infections but did not know what the clusters of microglia he saw were
Pío del Río Hortega, a student of Santiago Ramón y Cajal, first called the cells “microglia” around 1920
Rio Hortega went on to characterize microglial response to brain lesions in 1927 and note the “fountains of microglia” present in the corpus callosum and other perinatal white matter areas in 1932
After many years of research Rio-Hortega became generally considered as the “Father of Microglia”
1988, Hickey and Kimura showed that perivascular microglial cells are bone-marrow derived, and express high levels of MHC class Il proteins used for antigen presentation
What cells give rise to all macrophage populations and how?
Erythromyeloid progenitors (EMPs) derived from Yolk Sac give rise to all macrophage populations
Uncommitted EMPs express specific markers such as CD31+ and c-Kitt
EMPs develop via the macrophage ancestor population
- A1 (CD45+, CX3C1’ow, F4/80low) into the
- A2 (CD45+, CX3CR1hi, F4/80hi) progenitor population that commit to microglial cells
Amoeboid cells persist in the first 2 weeks of the postnatal brain where they gradually acquire the shape characteristic of microglia in the steady state
Initially, a small subset of master regulators of macrophage development, including, PU.1, C/EBPs, RUNX1, and IRF8, cooperatively drives specification and fate acquisition of EMPs into immature macrophages
In the brain, environmental factors such as CSF1, IL34, and TGFß play fundamental roles in shaping, maintaining, and reinforcing microglial identity.
Several transcription factors are specific or highly enriched in microglia, including SALL1, SALL3, MEIS3, and MAFB. However, their roles in microglia biology remain to be elucidated.
What is the evidence of a tripartite synapse?
Astroctes are excitable cells: in response to presynaptic or postsynaptic stimulation, astrocytes are capable of producing transient changes in their intracellular calcium concentrations through release of calcium stores from the ER
Astrocytes communicate bidirectionally with neurons: able to detect neurotransmitters and other signals released from neurons at the synapse and can release their own neurotransmitters or gliotransmitters
capable that are, in turn, capable of modifying the electrophysiological excitability of neurons
How do astrocytes regulate glutamatergic signalling?
Astrocytes participate in glutamate clearance (uptake) and provision
Astrocytes have glutamate transporters and recapture glutamate from the synaptic cleft, and they convert the glutamate into glutamine, which is then released back onto the presynaptic neurone
The presynaptic neurone will then use the glutamine to produce glutamate
Non-myelination Schwann cells function
Non-myelinating Schwann cells surround bundles of small-diameter neurons
Provide support and isolation from myelinated axons
Express specific surface markers L1 and NCAM not found in myelinating Schwann cells
What are perisynaptic Schwann cells?
Located at neuromuscular junction
They ensheath terminal axonal boutons
They respond to synaptic activity by Ca2+ waves
Able to modulate synaptic activity by regulating extracellular ion levels and also inducing post-synaptic
Ach receptor aggregation
What are olfactory bulb ensheathing cells (OBECs)?
Similar to non-myelinating Schwann cells, ensheath the axons of the olfactory nerve
Located at the interphase of the the CNS and PNS
They phagocytose axonal debris and dead cells
OBECs support and guide olfactory axons, grow through glial scars, and secrete many
neurotrophic factors
OBECs express glial markers such as GAP, s100, and p75, and radial glial markers such as nestin and vimentin
What is the myelin sheath?
Fatty insulated later that facilitates saltatory conduction
The myelin sheath is wrapped around axons to form concentric layers of lamellae
Longitudinally, myelin sheaths are separated by nodes of Ranvier: specialised naked axonal areas where action potentials are propagated
Myelin sheath between nodes called internodes
What are paranode and juxtaparanode?
Paranode:
- Region adjacent to the nodes of Ranvier on a myelinated axon.
- Located at the ends of each myelin segment (internode).
- Contains specialized junctions called paranodal axoglial junctions, formed by interactions between contactin, neurofascin-155 (NF-155), and Caspr (contactin-associated protein).
- Important for the attachment of the myelin sheath to the axon.
- Helps in maintaining the structure and function of the node of Ranvier.
Juxtaparanode:
- Region immediately next to the paranode, further away from the node of Ranvier.
- Contains a high density of voltage-gated potassium channels (Kv1).
- The junctions in this region are stabilized by the proteins Caspr2 (contactin-associated protein 2) and contactin-2 (also known as TAG-1, transient axonal glycoprotein-1).
- Contributes to the repolarization of the axon membrane after the passage of an action potential.
- Assists in stabilizing the electrical activity and preventing the backward spread of action potentials.
- Plays a role in the rapid and efficient conduction of nerve impulses.
What proteins are in the myelin sheath?
Proteins constitute 30%, mostly shared CNS VS PNS
In CNS main ones are MBP and PLP, which fuse the extracelullar and cytoplasmic faces. Also present in PIS myelin, but with unclear function
In PNS main protein is PO, mediating fusion of lamellae.
Also important PMP22 and Cx32
MAG present in both PNS and CNS, important for axon-myelin interaction, binding to specific gangliosides on the axonal surface
What is phase 1 of myelination?
Only if axon grows thicker than 0.7um (PNS) or 0.2um
(CNS) diameter
Loss of NCAM from axonal surface triggers myelination.
Similarly, L1 is expressed at premyelination, tagging axons to be myelinated (“ready for myelination”)
Partner molecules in myelinating cells not completely resolved
Contact with axons triggers differentiation of OPCs into Oligodendrocytes, starting to express myelin products (GalC, CNP, MBP, etc)
What is phase 2 of myelination?
Phase 2: Axon ensheathment and establishment of internodal segments
Extension of an initiator process that spirals along the axon using MAG and PLP to
“stitch”)
Myelination of multiple axons, followed by remodelling phase when non-ensheathing processes are lost
Initial clustering of Nat channels at nodes of Ranvier
What is phase 3 and 4 of myelination?
Phase 3/4: Remodelling and maturation
Loss of non myelinating processes
Subsequent wraps of myelin are produced, which fuse to each other dependent on PLP and MBP
Maturation of nodes of Ranvier (synchronised expression of molecular pairs at axon and myelin)
Microglia diversity and density
Microglia have a large variety of shapes and sizes (morphologies)
Microglia in humans are more dense in white matter than in grey matter (opposite in mice)
Microglia have different turnover rates in different regions of the brain
