Glial cells Flashcards
what are the 2 main pocket lineages of glial cell
microglia and macroglia
what are the four main functions of glial cells
- to surround neurons and provide physical support (hold them in place)
- to supply nutrients and oxygen to neurons (blood brain barrier)
- to insulate one neuron from another and facilitate synaptic communication
- to destroy and remove cell debris and unwanted molecules
what developmental roles do glia have
guiding migration of neurons in early development, and producing molecules that modify the growth of axons and dendrites
what roles do glia have as active participants in synaptic transmission
regulating clearance of neurotransmitter from cleft, releasing factors such as ATP which modulate presynaptic function and sometimes releasing neurotransmitter themselves
Glia are intimately correlated with ________. more advanced organisms -> more _______________.
Glia are intimately correlated with brain evolution. More advanced -> more percentage of brain is made out of glia
when were glial cells first noted and first named
First noted in 1824 and first named in 1856 (virchow)
the discovery of glial cells was credited to who
Rudolf Virchow
The first description of glia was by…
Rene Dutrochet
Otto Deiters claimed the defining feature of glial cells was what?
the lack of axons
who is Pio del Rio-Hortega
a student of Cajal, in 1920 classified the glia into four types: protoplasmic in gray matter, neuroglia in white matter, mesoblastic microglia, and interfascicular glia (what are now oligodendrocytes) – brought him a lot of trouble, he had to move.
what functions of glia cells were proposed by early neuroscientists and proved right
- ability to secrete chemicals (Nageotte)
- association with blood vessels (Golgi)
- morphological plasticity (Cajal)
- ability to electrically insulate (Cajal)
- role in neurotransmitter uptake and termination (Lugaro)
- role in pathology (Virchow).
which neuroglia are found in the peripheral nervous system
satellite cells, schwann cells
what neuroglia are found in the central nervous system
ependymal cells, oligodendrocytes, astrocytes, microglia
which glia originated from neuroectoderm
oligodendrocytes and astrocytes
which glial cells are derived from mesoderm/ yolk sac
microglia
which lineage of human mesenchymal stem cells do glia come from
myeloid
what are macroglia
the major supporting cells and include astrocytes, oligodendrocytes, and ependymal cells.
the endothelial blood brain barrier formation coincides with what?
the onset of vasculogenesis at 6 week of gestation
from 7 weeks gestations what features of the blood-CSF barrier are forms
show tight junctions similar to adult forms in many places (across choroid plexus, pia-arachnoid barrier and CSF-brain barrier)
what are radial glia
a common progenitor, they generate all types of glia. contribute to populating the brain and providing a scaffold for neuronal migration. they differentiate from neural progenitors early in development. somata in the ventricular zone and extending prolongations to the pia.
what does the key stage O2A progenitor give rise to
astrocytes and oligodendrocytes
what transcription factors control oligodendrocyte stepwise differentiation/maturation
notch1 and prox1
what is the precursor cell to oligodendrocytes
NG2 precursors
what major resident glial (precursor) cell population is retained throughout life
NG2 precursors
what cells give rise to schwann cell precursors
neural crest cells
what cells do neural crest cells give rise to
Schwann cell precursors, peripheral sensory and autonomic neurones and satellite cells of the dorsal root ganglia.
what determines whether immature schwann cells differentiate into myelinating or non myelinating cells
early association with large or small diameter axons (respectively)
what is wallarian degeneration
an active process of retrograde degeneration of the distal end of an axon that is a result of a nerve lesion (dedifferentiation of schwann cells is important) - two main causes 1) degenerative diseases affecting nerve cells, and 2) traumatic injury to the peripheral nerves.
what are key factors defining gliogenesis
Sox9 and NFIA
+ shh and notch
what is gliogenesis
the developmental process by which glial cells – astrocytes, oligodendrocytes, Schwann cells, microglia – are generated.
what are the two sites of constant neurogenesis
the lateral subventricular zone (SVZ) and the Dendate Gyrus of the hippocampus
what is the rostral migratory stream (RMS)
the major pathway by which progenitor cells migrate from the subventricular zone (SVZ) to the olfactory bulb (OB)
what protein is involved in astrocyte maturation
S100beta
what macrophage subpopulations are in the brain
microglial cell, meningeal macrophage, dendritic cell, choroid plexus macrophage, perivascular macrophage
what functions do microglial cells have
immunosurveillance, synaptic pruning, neuromodulation, phagocytosis
what are the two primary routes of microglial regulation of brain development
the release of diffusible factors and phagocytosis. phagocytize many products in the brain, including synaptic elements, living cells, dying or dead cells, and axons (remove excess cells (+in neurogenesis in adulthood) and excess synaptic contacts (up to 20yoa))
what two glial cells help regulate synaptic function
astrocytes and microglia
what are the basic characteristics of microglial population distribution
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 50000mm3
microglial repertoire of immune sensors and reactants allows…….
……rapid and plastic reactions to disruptions of the brains homeostasis
who was generally considered the father of microglia
Pio del Rio Hortega
what’s the location that perivascular microglial cells are derived showed by Hickey and Kimura in 1988
bone marrow
when did Franz Nissl develop Nissl staining
1880
where are the fountains of microglia described by Rio Hortega located
in the corpus callosum and other perinatal white matter
what are erythromyeloid progenitors (EMPs)
arise from the yolk sac endothelium, just prior to vascular remodeling, and are the source of adult/post-natal tissue resident macrophages
what specific markers do uncommitted EMPs express
CD31 and c-Kit
what happens to amoeboid cells in the postnatal brain
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.
what subset of master regulators help cooperatively drive specialisation and fate acquisition of EMPS into immature macrophages
PU.1, C/EBPs, RUNX1, and IRF8
what are the functions of astrocytes
- Neurogenesis and gliogenesis in the adult brain
- Neuronal guidance in development: role of radial glia
- Regulation of synaptogenesis and synaptic maturation in development?
- Microarchitecture of the brain. Define and connect domains that include neurons, synapses and blood vessels.
- Creation of the blood-brain barrier
- Synaptic modulation
astrocytes form local domains by connecting via ____________ so there is no need for extracellular communication components
gap junctions
what are Bergmann cells
a unipolar astrocyte in the cerebellum, displaying a tight association with Purkinje cells
how do astrocytes act as the third in the tripartite synapse
astrocytes are excitable cells: in response to pre/post synaptic stim they can produce transient changes in their intracellular Ca2+ concs and release Ca stores from ER
astrocytes communicate bidirectionally: able to detect neurotransmitters + other signals and can release their own NTs or gliotransmitters that can modify the electrophysiological excitability of neurons
Communication with other astrocytes modulating distant synapses
what role do astrocytes have in glutamate transmission
participation in Glutamate clearance (by converting it into glutamine by glutamine synthetase (GS))
can drive synchronous depolarisation
modulate synaptic communication by gliotransmitters
what are the ATP gliotransmitter receptors present in neurons and astrocytes
ATP targets P2X receptors, P2Y, and A1 receptors.
what are the two major gliotransmitters
glutamate and ATP
what functions does ATP have as a gliotransmitter
insertion of AMPA receptors into the postsynaptic terminal, paracrine activity through calcium waves in astrocytes, and suppression of synaptic transmission
give an example of astrocytes response selectively in the hippocampal stratum oriens
Astrocytes of the hippocampal stratum oriens form tripartite synapses with axonal projections from the alveus.
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
(do respond to Glu but only by synaptic activity originating from the Schaffer collateral)
how are astrocytes involved in synaptic plasticity
astroglial release of glutamate, ATP, and cytokines likely alters the survivability and functioning of newly formed connections.
how do astrocytes integrate and modulate info from their synaptic inputs
produce changes in their intracellular calcium concentrations that are non-linear with the strength of synaptic input.
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.
when a lesion occurs on the spinal cord, what determines the severity of paralysis
the placement of the lesion - the higher up it is the more wide spread the paralysis as it prevents any downstream signaling
what is a glial scar
a reactive cellular process (involving astrogliosis) formation of scar tissue around an injury to the central nervous system - causes interruption to neural repair and regrowth - a balance of support and inhibition
what is the growth cone?
A growth cone is a large actin-supported extension of a developing or regenerating neurite seeking its synaptic target - drive actin growth
what is the main cellular component of glial scars
reactive astocytes
what potential mechanisms explain why transected axons fail to regrow spontaneously across severe tissue lesions
potential mechanisms include: (i) reduced intrinsic growth capacity of mature CNS neurons; (ii) absence of external growth stimulating and supporting factors; and (iii) presence of external inhibitory factors associated with myelin, fibrotic tissue or astrocytic scars
how do atrocytes contribute to failure of axonal growth after central nervous system injury
they provide both physical and chemical distruption: generation of a capsule to contain the injury turns into a cystic cavity where debris like blood vessels etc is remove and the cavity is filled with cystic fluid. this is a physical inturruption that stops regrowth
release of chemcials that interupt axonal growth include CSPGs
what chemcials contribute to the potential of astrocytes to help axonal regrowth after glial scar formation
Integrin, Laminin, N cadherin
injection of what two proteins in hydrogel has been shown to promote aconal guidence and activation of more protective atrocytes
neurotrophin-3 and BDNF
what is the first defence when the central nervoys system is injured
astrocytes increase in nymber and change morphology and produce fribrotic tissue to try and ocntain the injury
removal of what protein could allow for spontaneou dregeneration of axons
pTEN
what are the myelination cells of the nervous sytem what are two major differences
Oligodendrocytes (all myelination) in CNS, each myelinating multiple axons (average 10 axons per cell) Schwann cells (myelinating and non myelinating), each wrapping aorund a single cell
myelination is dependent on ______ (visaversa)
axonal diameter
what is a pneumbra in neuroscience
the penumbra is the part of the brain that is sandwiched between brain regions committed to die and those that receive enough blood to communicate. Therefore, it is ischemic brain tissue that has just enough energy to survive for a short time but not enough to communicate and function
- reversibly injured brain tissue around ischemic core
the ___________ of axon (diameter) and the _________ (number of lamellae) are intedependent, resulting in the _____ of axons
The radial growth of axons (axon’s diameter) and the myelin sheath (number of lamellae) are interdependent, resulting in the g-ratio of axons (1:10)
what is the g ratio of axons and what is the optimal ratio
ratio of the inner axonal diameter to the total outer diameter -a functional and structural index of optimal axonal myelination.
0.6
describe the interdepedence of glia and 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
what are non-myelinating schwann cells (what markers do they possess not found on 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 (teloglia)
(at NMJ) ensheath terminal axonal boutons function in synaptic transmission, synaptogenesis and nerve regeneration
how do perisynatpic schwann cell repsond and modulate synaptic transmission at NMJs
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 axons of the olfactory nerve - located in the interphase of the CNS and PNS
what do olfactory bulb ensheathing cells do
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
what is the myelin sheath
Fatty insulated later that facilitates saltatory conduction
wrapped around axons in concentric layer called lamellae. longitudinally separated by nodes of Ranvier (myelin between nodes are the internodes)
what is the composition of the myelin sheath
Lipids constitute 70% of myelin, with cholesterol being the main component, with phospholipids and glycolipids (ratio 4:3:2)
Rich in glycosphingolipids, mainly GalC
Proteins constitute 30%, mostly shared CNS vs PNS
what are the difference in composition between CNS and PNS myelin sheath
Composition of gangliosides differs; in CNS=GM4 PNS=LM1, GM3
Main CNS proteins are MBP and PLP
Main PNS protein is P0 and PMP22 and Cx32
what do MBP and PLP do in the CNS myelin sheath
fuse the extracellular and cytoplasmic faces
what does P0 do in the PNS
mediates fusion of lamellae
what is MAG and where is it found
In the myelin sheath of both the PNS and CNS - a protein important for myelin-axon interaction binding to specific gangliosides on the axonal surface
what are the four phases of myelination
Axon contact
Axon ensheathment and establishment of internodal segments
Remodelling
Maturation
what occurs during the first stage of myelination?
if axon grows thicker than 0.7mm (PNS) or 0.2mm (CNS)
Loss of NCAM from axonal surface triggers myelination
Contact with axons triggers differentiation of OPCs into Oligodendrocytes starting to express myelin products (GalC, CNP, MBP etc)
what protein tags axons to be myelinated (‘ready for myelination’)
L1 expressed premyelination and tags axons to be myelinated
what occurs during phase two 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”)
adhesion/ recognition signals
Myelination of multiple axons
Initial clustering of Na+ channels at nodes of Ranvier
what occurs during the third and fourth stages of myelination
Remodeling and maturation
Subsequent wraps of myelin are produced, which fuse to each other dependent on PLP and MBP
Loss of nonmyelinating processes
Maturation of nodes of Ranvier (synchronised expression of molecular pairs at axon and myelin)
Myelin compaction - radial and longitudinal growth
what three things drive the pathophysiology of multiple sclerosis
Autoimmunity: generation of autoantibodies against myelin components, commonly involves white matter and direct damage of oligodendrocytes causing demyelination (remyelination in early phase but not complete (relapse leads to impaired remyelination)
BBB breakdown: damage drives entrance of immune cells predominantly T cells
Chronic inflammation: demyelination triggers T cell attack of 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 glia
what role do glia play in multiple sclerosis
astrocytes recruit lymphocytes and cause tissue damage (gliosis of glial scar)
microglia cause degeneration of chronically demyelinated axons, redistribute sodium channels and remyelinate after demyelination and axonal transduction (also cause axonal transduction
what is microglial surveillance
microglia to swarm to the area of injury immediately
React immediately, first line of defense. Extend processes towards the injury. If bad enough they will proliferate around it. Preserve neurons by keeping them away from the injury
what three ways can microglia vary
Morphological diversity
Regional density
Different turnover rates
what is the difference in microglial populations between humans and mice
In humans more microglia in white matter than grey matter, the same ratio across the brain
In mouse more in grey than in white. Some regions have higher turnover rates than other
what three general roles do microglia have in multiple sclerosis
phagocytosis of myelin, antigen presentation to T cells and release of proinflammatory cytokines in active lesions
what are the two main function of microglia
- Ability of microglia to remove synapse: whole/bits? Not sure. Evidence for eating synapses
- Ability to phagocytose whole dead cells, clear excess of apoptopic cells. Before it becomes toxic
what are the five subpopulations of microglia
surveillant microglia proliferating microglia pruning microglia neuromodulatory microglia phagocytic microglia
what are the two types of microglia lineage determining transcription factors are there that cause diversity in microglia
environment-dependent factors and core macrophage factors
what role do microglia have in the development of neural connections throughout the dorsal lateral geniculate nucleus in development
• 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
- Microglia with remove projections from the ipsolateral side (so that the contralateral connections remain)
perturbation of microglia activity into the wiring of early forebrain development affects the…
(cell depletion or cx3cr1−/−, CR3−/−, DAP12−/−) affects the outgrowth of dopaminergic axons in the forebrain and the laminar positioning of subsets of neocortical interneurons
what cells control apoptotic cell clearance in developing brain
microglia cause significant death of progenitors and the extra neurons made during development
what triggers the specification of disease-associated microglia from the homeostatic state
trem2
what is involved in the development of Alzheimers disease
innate immunity (genes fromcomplemetn pathway) drives alzheimers disease as well as dramatic phenotypic change of microglia to disease associated microglia by trem2
what factor is the main driver of microglial proliferation causing Prion disease, ALS and FTD - and it a potential target for treatment
CSF1
- targetting may prevent neurodegeneration and behaviour
what progenitors do microglia develop from
yolk sac progenitors in a stepwise program
what are the major roles of microglia
development of the brain, surveillant/homeostatic profile, synaptic modulation, brain immunity
