Glial cells Flashcards
(154 cards)
1
Q
What this topic is about and what you’ll learn
A
- Development of glial lineages
- Developmental timing and regulation of differentiation
- Roles of glia in the developing brain
- Control of synaptic pruning, neurogenesis and neuronal differentiation
- Roles of astrocytes in the healthy, ageing and diseased brain. Regulation of BBB and synaptic function
- Roles of microglia in the healthy, aging and diseased brain. Regulation of immune-to-brain communication, neuronal physiology, inflammatory activation in brain disease
- Roles of myelinating glial cells in the peripheral and CNS. Demyelinating diseases
- Methods to study the roles of glial cells in vitro and in vivo
2
Q
LO
A
- Describe the timing and steps of the developmental formation of the individual glial cell types in the nervous system
- Provide an overview of the different lineages of glial cells, and the critical factors defining lineage commitment and differentiation
- Detail the roles played by glial cells in the developing brain, including their contribution to synaptic pruning, neurogenesis and neuronal differentiation and their regulation of the BBB
- Describe the functions played by the different glial cells types in the adult and ageing nervous system
- Describe and give examples of critical roles of glial cells in brain disorders like Alzheimer’s disease, MS or stroke. Discuss the contribution of glial cell activation to the progression of brain disorders
3
Q
Tell me the two types of neural cells and their subdivisions
A
Although glia cells DO NOT carry nerve impulses (Action potentials) they do have many important functions. In fact, without glia, the neurons would not work properly
4
Q
What are the four main functions of glial cells?
A
- To surround neurons and provide physical support (hold them in place)
- To supply nutrients and oxygen to neurons
- To isolate one neuron from another and facilitate synaptic communication
- To destroy and remove cell debris and unwanted molecules
5
Q
What does the glia have important role in?
A
Glia has important development roles, guiding migration of neurons in early development, and producing molecules that modify the growth of axons and dendrites
6
Q
What are glia also active participants in?
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Glia are also active participants in synaptic transmission, regulating clearance of neurotransmitter from the synaptic cleft, releasing factors such as ATP which modulate presynaptic function, and even releasing neurotransmitters themselves
7
Q
What else does glia have a fundamental role in?
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Glia plays a fundamental role in brain disease and degeneration, defining the pathophysiology trajectory
8
Q
Phylogenetical advantage of glial cells
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9
Q
Historical perspectives of glia cells
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- The discovery of neuroglia is usually credited to Rudolf Virchow, a mid-nineteenth century German anatomist… but the first description of the glia was much earlier, when French physician Rene Dutrochet noted small globules among the large globules of the mollusk nervous system in 1824
- Virchow, in 1856, was the first to name these structures, calling them first glia from the Greek γλία and γλοία “glue” and later “nevernkitt,” meaning nerve-glue and translated to “neuroglia.”
- Otto Deiters also had a role in the earliest descriptions of non-neuronal nervous tissue, claiming the defining feature of these new cells was their lack of axons (Some of the cells he found meeting this description were in fact incompletely stained neurons)
- Most of the debate and disagreement around classification (embryonic origins)
- Ectodermic origin: Deiters was the first to suggest this, and were thus epithelial rather than connective tissue, as Virchow thought
- Andriezen recognised two types of glia in 1893, ectodermal fibrous glia in the white matter and mesoblastic protoplasmic glia in the grey matter
- Ramon y Cajal agreed with the classification but argues that both came from the ectoderm. Ramon y cajal also notes a non-glial third element without dendrites or polarity, which probably resulted from a staining artifact
- In 1920, Pio del Rio-Hortega, a student of cajal, classified the glia into four types: protoplasmic in grey matter, neuroglia and interfascicular glia) what are now oligodendrocytes) … what brought him a lot of trouble!
- See Sierra et al 2016 Glia, for full translation of Rio-Hortega work
10
Q
Tell me some of the functions that have been discovered about glia cells over history?
A
Many of the functions are now recognised, however, were proposed by the earliest neuroscientists, such as:
- Glias ability to secrete chemicals (Nageotte)
- Their association with blood vessels (Golgi)
- Their morphological plasticity (Cajal)
- Their ability to electrically insulate (Cajal)
- Their role in neurotransmitter uptake and termination (Lugaro)
- Role in pathology (Virchow)
11
Q
Macroglial lineages and development: traditional view
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12
Q
Tell me the neuroglia found in the PNS
A
Satellite cells
Schwann cells
13
Q
Tell me the neuroglia found in the CNS
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Ependymal cells
Microglia
Astrocytes
Oligodendrocytes
14
Q
Tell me the following about satellite cells
- what are the surrounded by
- what do they regulate
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15
Q
Tell me the following about schwann cells
- what are they surrounded by?
- What are they responsible for?
- what do they participate in?
A
16
Q
What is the role of oligodendrocytes?
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17
Q
Tell me the following about astrocytes
- what do they maintain
- what do they provide
- what do they regulate
- what do they absorb
- what do they form
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18
Q
What do microglia remove?
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19
Q
What do the ependymal cells line and what do they assist in?
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20
Q
Tell me what type of cells satellite cells are and where they reside
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satellite cells are glial cells that live in ganglia. They are the only cell type there
21
Q
Tell me the divisions of the brain i.e. forebrain, midbrain and hindbrain
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22
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Developmental layers
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23
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Brain development
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24
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Lineages and fate choice
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25
What are radial glial cells?
Radial glial cells, or radial glial progenitor cells (RGPs), are bipolar-shaped progenitor cells that are responsible for producing all of the neurons in the cerebral cortex. RGPs also produce certain lineages of glia, including astrocytes and oligodendrocytes.
cells which have bodies next to ventricle, prolongation goes over developing cortex
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What do radial glia cells differentiate from?
They differentiate from neural progenitors early in development, with somata in the ventricular zone and extending prolongations to the pia
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What can radial glial cells give rise to?
They can give rise to all cell lineages, contributing to populate the brain and providing a scaffold for neuronal migration
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Diagram of cells from embryo to adult
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What are key stage O2A progenitor cells?
Key stage O2A progenitor that can give rise to astrocytes and oligodendrocytes
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What do cells acquire as the migrate and colonise specific regions?
Cells acquire identity as they migrate and colonise specific regions, defined by the factors they encounter
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Tell me about oligodendrocyte differentiation
Oligodendrocyte differentiation is a stepwise programme from **NG2 precursors** (retained throughout life) to mature myelinating oligodendrocytes
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What do cell do neural crest cells give rise to?
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
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What can immature schwann cells differentiate into?
Immature schwann cells differentiate into myelinating or non-myelinating depending on early association with large or small diameter axons, respectively
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What is schwann cell de-differentiation an important process during?
Their de-differentiation is an important process during Wallerian degeneration
35
Tell me about the stages of astrocyte lineage development
Unlike OLs, 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 (see specific lectures), suggesting the number and role of subpopulations is yet to be defined
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Tell me about astrocyte maturation
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New insights into macroglial lineages
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Cajal and his insight into adult neurogenesis redefining embryonic development
“one development was ended, the founts of growth and regeneration of axons dried up irrevocably. In adult centres the nerve paths are fixed, ended, immutable. Everything may die, nothing may be regenerated. It is for science to change, if possible, this harsh decree” (Ramon y Cajal 1913- 1914)
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Adult neurogenesis
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Tell me about hippocampal neurogenesis
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What is neurogenesis?
Neurogenesis is the process by which new neurons are formed in the brain. Neurogenesis is crucial when an embryo is developing, but also continues in certain brain regions after birth and throughout our lifespan.
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Cell reprogramming
Cell reprogramming can be a target for neurodegenerative diseases such as Alzheimer’s to help replace hippocampal cells
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**Summary**
* **Historical overview of the definition of glial cells and their functions**
* **Relevance and diversity of glial cells**
* **Main theories for the developmental specification of glial populations**
* **Main features of the development of oligodendrocytes, Schwann cells and astrocytes**
* **New insights into multipotency and lineages**
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**LO for lecture 2**
* Introduction and quick history
* Microglial development and functions
* New insights and open questions
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Are microglia macrophages?
Disclosure: microglia ARE macrophages… and, actually only one of the brain’s immune populations
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Immune census of the brain
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Tell me the macrophage subpopulations in the brain
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Macrophage subpopulations in the brain
49
Tell me the possible roles of the following...
* Meninges (BBB)
* Perivascular space
* Choroid plexus (Blood-CSF barrier)
* Brain Parenchyma
50
Tell me the basic characteristics of the microglial population
* **Ramifies 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 50000µm3
* Equipped with a repertoire of **immune “sensors” with “reactants”**, allowing rapid and plastic reactions to distributions of the brains homeostasis
51
What are the systemic sensing microglia?
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Brief history of microglia
* 1880: Nissl staining developed by **Franz Nissl**, allowing visualisation of cells including microglia
* **Nissl and Robertson**, first described microglial cells, showing that microglia are related to macrophages. Stābchenzellen (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 characterise microglial response to brain lesions in 1927 and not 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 II proteins used for antigen presentation
53
Tell me what Rio Hortega assumed and discovered and now whats considered
54
Colonisation and lineages
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What are EMPs and what are they derived from? What does this give rise to?
Erythromyeloid progenitors (EMPs) derived from yolk sac give rise to all macrophage populations
56
Tell me about the brain's colonisation
The brain is colonised directly (without relay in the liver) and earlier than other organs
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Uncommitted EMPs express what?
Uncommitted EMPs express specific markers such as **CD31+ and c-Kit+**
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What do EMPs develop via?
EMPs develop via the macrophage ancestor population A1 (CD45+, CX3CR1low, F4/80low) into the A2 (CD45+, CX3CR1hi, F4/80hi) progenitor population that commit to microglial cells
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Specification of microglia during development
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Where do **Amoeboid cells** persist? What do they acquire?
Amoeboid cells persist during the first 2 weeks of the postnatal brain where they gradually acquire the ramified shape characteristic of microglia in the steady state
61
What are the initial small subset of master regulators of macrophage development?
What do they drive?
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
62
In the brain, environmental factors such as CSF1, IL34 and TGFbeta play fundamental roles in what?
In the brain, environmental factors such as CSF1, IL34 and TGFbeta play fundamental roles in shaping, maintaining and reinforcing microglial identity
63
Sevel TF are specific or highly enriched in microglia. Name these TF
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
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Transcriptional and functional diversity
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Microglia diversity throughout the mouse lifespan
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Transcriptional and functional diversity
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... Transcriptional and functional diversity
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... Transcriptional and functional diversity
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What is the adult microglial population maintained by?
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Current model for microglial dynamics?
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**Summary of lecture II**
* **The immune compartment of the brain is complex and (very) diverse**
* **Microglia have key functions for brain development and homeostasis**
* **Microglia develop from YS progenitors in a stepwise program**
* **The majority of brain macrophages are not replaced during adulthood and health ageing**
72
Tell me 7 functions of astrocytes?
1. Neurogenesis and gliogenesis in the adult brain
2. Neuronal guidance in development: role of radial glia
3. Regulation of synaptogenesis and synaptic maturation in development? (see Chung et al., 2013)
4. Structural function: microarchitecture of the brain. Astrocytes define and connect domains that include neurons, synapses and blood vessels
5. Communication through gap junctions
6. Creation of the blood-brain barrier
7. Synaptic modulation
73
Whats the tripartite synapse?
Tripartite synapse refers to the functional integration and physical proximity of the presynaptic membrane, postsynaptic membrane, and their intimate association with surrounding glia as well as the combined contributions of these three synaptic components to the production of activity at the chemical synapse
74
Rougly 60% of axon-dendritic synapses are surrounded by what?
Roughly 60% of axon-dendritic synapses surrounded by astroglia membranes (hippocampus)
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80% of large, perforated synapses (the most frequenct type) are enwrappyed by what?
nb. Perforated synapses belong to a special morphological variety of synaptic junctions, characterized by the presence of aligned discontinuities (gaps )
astrocytes
76
Using the example of cerebellum tell me two cells that interact and what they enwrap?
Example of the cerebellum, interaction of Purkinje cells with Bergmann cells (astrocytes of the cerebellum), each cell enwrapping 2000-6000 synaptic contacts
77
What is the evidence for tripartite synapses?
* Astrocytes and 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 that are, in turn, capable of modifying the electrophysiological excitability of neurons
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The tripartite synapse glutamatergic signalling
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Astrocytes particiapate in the clearance and provision of what?
Gln as a substrate
80
What is Gln main target receptors?
Glu main target receptors include **Kainate receptors**, **metabotropic glutamate receptors** (mGluRs), and especially **NMDA receptors**
81
Tell me some other functions of the gliotransmitter?
Other functions of this gliotransmitter include **synchronous depolarisation**, increasing the frequency of postsynaptic currents, and also increasing the **likelihood of release and frequency of AMPA-receptor-dependent postsynaptic currents**
82
What receptors does ATP target?
ATP targets **P2X receptors, P2Y, and A1 receptors**
83
Tell me several of ATPs functions?
ATP has several functions including...
* **insertion of AMPA receptors** into the postsynaptic terminal
* **paracrine activity** through calcium waves in astrocytes
* **suppression of synaptic transmission**
nb. Paracrine signaling is a form of cell signaling or cell-to-cell communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells
84
Tell me about the mechanism of ATP release
The mechanism of ATP release is not well understood.
Unclear whether or not ATP-mediated gliotransmission is calcium-dependent, but believed that ATP release is partly dependent on **Ca2+ and SNARE proteins** with **exocytosis** being the suggested method of release
85
Astrocytes are capable of responding to selective stimuli. Astrocytes of the hippocampal stratum oriens (horizonal interneurons) form what? with what?
Astrocytes are capable of responding selectively to stimuli: Astrocytes of the hippocampal stratum oriens (horizontal interneurons) **form tripartite synapses with axonal projections from the alveus.**
86
What can the alveus projections form?
what do the astrocytes of this region respond with?
What receptors do they have, but what else to they respond to?
The alveus projections can form either **glutamatergic or cholinergic synapses** with the stratum oriens,
but the astrocytes of this region respond with **changes in calcium concentration only to cholinergic activation of alveus projections**
(they DO have Glu receptors as they also respond to glutamatergic synaptic activity originating from a different brain region, the Schaffer collateral)
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What do astrocytes do from their synaptic inputs?
integrate and modulate information
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What do the hippocampal stratum oriens respond to?
What does this produce?
The hippocampal stratum oriens astrocytes, which r**espond to synaptic activity from glutamatergic neurons** originating in the Schaffer collateral and cholinergic neurons originating in the alveus, produce **changes in their intracellular calcium concentrations that are non-linear** with the strength of synaptic input.
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From the astrocytes synaptic input, what are these same stimuli capable of producing?
Additionally, these same stimuli are capable of producing either a **potentiated calcium concentration response at low frequencies of stimulation or a depressed calcium concentration response at high frequencies of stimulation.**
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What is the blood-brain barrier?
Barrier between the intracerebral blood vessels and the brain parenchyma
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What is the BBB formed by?
Formed by tight junctions between endothelial cells and astroglia end feet
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Where are the BBB present?
Present throughout the brain **except** circumventricular organs (CVOs), neurohypophysis, pineal gland, subfornical organ and lamina terminalis, involved in neuroendocrine signalling
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Every solute that crossed the BBB must pass through what?
What does it have selective permeability to?
Every solute that crossed the BBB must pass through endothelial cells: selective permeability to essential nutrients to enter and to metabolites to leave
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Specific transporters at the endothelial cells include what...?
* Energy-dependent ABC transporters: excrete xenobiotics (impermeability to drugs, antibiotics, etc)
* Amino acid transporters
* GLUT1 glucose transporters
* Ion exchangers
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Specific transporters at the astrocyte endfeet include what...?
* Glucose transporters: uptake and distribution to neurons
* K+ channels (Kir4.1)
* Water channels (aquaporin 4)
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Inflammation and axon injury: the glial scar
What is the glial scar?
Glial scar formation (gliosis) is a reactive cellular process involving astrogliosis that occurs after injury to the central nervous system. As with scarring in other organs and tissues, the glial scaris the body's mechanism to protect and begin the healing process in the nervous system
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Glial scar formation
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The glial scar as a balance of inhibition and support
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Growth cone
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Astrocyte scar
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**Summary II**
* **Astrocytes provide basic structural and functional support to the brain, operating as a network**
* **Astrocytes are synaptically competent, influencing and regulating neuronal communication**
* **Astrocytes, through their interaction with endothelial cells at the BBB, contribute to preserving tissue homeostasis**
* **Astrocytes form a glial scar after traumatic brain injuries, contributing (?) to the impaired regeneration**
102
**LO**
* **Schwann cells and OBECs**
* **Structure and composition of myelin**
* **Myelination**
* **Multiple sclerosis**
103
What cells produce myelin?
**Schwann cells in the PNS** (one schwann cell forms a single myelin sheath)
**Oligodendrocytes in the CNS** (each myelinating multiple axon average of roughly 10 axons per cell)
Oligodendrocytes do this by creating the myelin sheath. A single oligodendrocyte can extend its processes to 50 axons, wrapping approximately 1 μm of myelin sheath around each axon; Schwann cells, on the other hand, can wrap around only one axon
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Are schwann cells only myelinating?
Schwann cells are myelinating and non-myelinating
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What is myelination dependent on?
Tell me about the relationship between radial growth of axons and the myelin sheath?
**Myelination is dependent on axonal diameter** (and vice versa)
The radial growth of axons (axon’s diameter) and the myelin sheath (number of lamellae) are **interdependent**, resulting in the g-ratio of axons: number of myelin lamellae (1:10), which is a constant in the CNS and PNS.
106
Tell me about the interdependence of glia-axons
Interdependence of glia-axons: the loss of axons results in degeneration of oligodendrocytes and de-differentiation of Schwann cells; conversely, axons degenerate in the absence of appropriate support from Schwann cells and oligodendrocytes.
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What do non-myelinating Schwann cells surround?
Bundles of small-diameter neurons
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What do schwann cells provide?
Support and isolation from myelinated axons
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What do schwann cells express?
Specific surface markers L1 and NCAM not found in myelinating schwann cells
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Where are perisynaptic schwann cells located and what do they ensheath?
Perisynaptic Schwann cells (at **NMJ**) ensheath terminal axonal boutons
Specialized glial cells, the terminal or perisynaptic Schwann cells (PSCs), are located to NMJ in skeletal muscles, where they form a 'tripartite' synapse together with the presynaptic motor nerve terminal and the postsynaptic specialization of muscle fibers
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What are the three types of schwann cells?
112
What do perisynaptic schwann cells respond to and therefore modulate?
* 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
113
Tell me about Olfactory bulb ensheathing cells (OBECs)?
Where are they located?
* Similar to non-myelinating Schwann cells, ensheath the axons of the olfactory nerve
* Located at the interphase of the the CNS and PNS
114
Tell me the role of OBECs... main function, what they support and what they express
* 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 **GFAP, s100, and p75, and radial glial markers such as nestin and vimentin**
115
What is myelin sheath?
A fatty insulated layer that **facilitates saltatory conduction**
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What is the myelin sheath wrapped around?
It is wrapped around axons to form concentric layers of **Lamallae**
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What are myelin sheaths separated by longitudinally?
**Nodes of Ranvier**
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Whats are nodes of ranvier?
specialised naked axonal areas where action potentials are propagated. Myelin sheath between nodes called internodes
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Whats key for saltatory conduction?
Molecular interactions at the Paranode and Juxtaparanode define the clustering of K+ and Na+ channels that are key for the saltatory conduction
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What is myelin made up of?
What is it rich in?
Where does the gangliosides differ between?
* **Lipids constitute 70% of myelin**, with **cholesterol** being the main component, with **phospholipids** and **glycolipids** (ratio 4:3:2)
* Rich in **glycosphingolipids**, mainly **GalC which is used as a marker**
* Composition of gangliosides differs from CNS vs PNS; in **CNS=GM4 PNS=LM1, GM3**
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Proteins constitute 30%, mostly shared CNS vs PNS
Tell me about the main protein in CNS and PNS
What is the main protein present in both PNS and CNS
* Proteins constitute 30%, mostly shared CNS vs PNS
* In **CNS** main ones are **MBP and PLP**, which fuse the extracellular and cytoplasmic faces. Also present in PNS myelin, but with unclear function
* In **PNS** main protein is **P0**, 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
122
What are the 4 phases of myelination?
1. Axon contact
2. Axon ensheathment and establishment of internodal segments
3. remodelling and maturation
4. remodelling and maturation
123
Tell me about phase 1 of myelination (Axon contact)
* Only if axon grows thicker than 0.7mm (PNS) or 0.2mm (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)
124
Tell me about phase 2 of myelination (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 Na+ channels at nodes of Ranvier
125
Tell me about phase 3/4 of myelination (remodelling and maturation)
* 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)
126
What is autoimmunity?
**Autoimmunity:** The immune system develops and autoimmune attack of the CNS, forming plaques or lesions.
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Tell me about multiple sclerosis autoimmunity
* Generation of autoantibodies against myelin components
* Commonly involving white matter
* Direct damage to oligodendrocytes, causing demyelination
* Remyelination in early phase but not complete
* Relapses lead to impaired remyelination
128
Tell me about **BBB breakdown** with MS
BBB breakdown: damaged BBB drives the entrance of immune cells, predominantly T cells.
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Tell me about **Chronic inflammation** with MS
**Chronic inflammation:** demyelination triggered by T cells attacking myelin, driving recruitment of other inflammatory cells by releasing cytokines and antibodies. BBB leakage causes swelling, activation of macrophages and a vicious cycle of inflammation and damage driven by astrocytes and microglia
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MS early and late disease
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Role of glia in MS
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**Summary**
* **Similarities and differences between Schwann cells and Oligodendrocytes**
* **Basic structure-function of myelin**
* **Crosstalk of axons and myelinating cells define myelination**
* **The interaction of oligodendrocytes (and OPCs) with other glial cells determines the progression of demyelinating diseases**
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**Lecture plan**
* **Functional diversity of microglia**
* **Roles of microglia in the developing and adult brain**
* **Roles of microglia in chronic neurodegeneration**
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Recap: macrophage subpopulation in the brain
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Recap: development
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Systemic sensing microglia
137
Tell me the reasons for microglial diversity
* Morphological diversity
* Regional density
* Different turnover rates
138
Transcriptional and functional diversity: mouse
139
Tell me about transcriptional and functional diversity: mouse
* Core transcriptional module, with considerable homology to mouse microglia
* Environment-dependent transcriptional module, including GWAS gene hits for AD/PD/MS
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Synaptic pruning and apoptotic cell clearance
141
Explain this experimental paradigm of synaptic pruning
* Retinal ganglion cells (RGCs) form synaptic connections with relay neurons throughout the dorsal lateral geniculate nucleus (dLGN) of the thalamus
* During the postnatal pruning period, RGC synaptic inputs originating from the same eye as well as between eyes compete for territory throughout the dLGN
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Synaptic pruning: complement dependent?
143
Tell me about wiring of forebrain in early development
Perturbing microglial activity (cell depletion or cx3cr1−/−, CR3−/−, DAP12−/−) affects the outgrowth of dopaminergic axons in the forebrain and the laminar positioning of subsets of neocortical interneurons
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Apoptotic cell clearance: from development to adult
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Tell me some of the immune roles of microglia
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Innate immunity is a driver and/or a cause of Alzheimer's disease
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Temporal evolution of the microglial profile in Alzheimer's disease
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Microglia vs BM-derived monocytes?
Recruitment of bone-marrow derived cells into the ALS brain requires preconditioning (i.e. irradiation)
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Microglia as nesessary transducers of amyloid beta pathology
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**Summary**
* **The microglial population is phenotypically complex, displaying regional and age-dependent diversity**
* **Microglia has major roles in the development of the brain, including circuit refinement**
* **In the healthy adult brain, microglia adopt a surveillant/homeostatic profile, with postulated functions in synaptic modulation**
* **Microglia re-activate their immune functions upon disruption of the homeostasis (challenge, injury, disease)**
* **Microglia are central to the progression of chronic neurodegenerative diseases**
