NEURAL cells = neurons and glia Neuronal cells = neuron GLIA =
Macroglia and Microglia MACROGLIA ASTROCYTES RADIAL GLIA
OLIGODENDROGLIA (CNS myelin) SCHWANN CELLS (PNS myelin)
Embryonic Origin
Neurons + Astrocytes and Oligodenrocytes from the neural
tubeSchwann Cells are from the Neural CrestMicroglia derived from
macrophages (ie blood)
Gliogenesis
Glia of The CNS
Microglia
1. Nucleus of microglia 2. Process of microglia3. Lysosome4.
Capillary5. Pericyte
Evidence for the monocytic origin of microglia
Bone marrow chimeras show that the brain becomes populated by
donor specific cells of the haemopoietic origin Exogenously
labelled monocytes enter the developing CNS and immunocytochemical
studies show the changes in morphology as monocytes transform to
microglia. Microglia share many cell surface and cytoplasmic
antigens exclusively restricted to macrophages Immunocytochemical
studies of transplanted CNS tissue show that the transplanted CNS
tissue becomes populated by microglia bearing host specific makers
for myelomonocytic cells.
Types of Microglia
Ameboid. Round cells - clustered, found in development. Develop
in cultures of glia derived from neonatal brain. Concentrated in
the corpus collosum. Proliferate. Ramified Adult form found in the
brain - having numerous, fine processes. Found throughout the brain
- resting. Dont proliferate when restingActivation states of adult
microglia can identified by the structure and also the antigens
expressed by them. Resting - fine processes OX-42 Activated - thick
processes, vimentin, OX-42, proliferate, migrate Phagocytic -
globular, vimentin, OX-42, OX-8, proliferate
- Resting microglia in normal brain- Activated microglia in
diseased brain(marked induction of indolamine 2,3-dioxygenase)-
Phagocytic macrophages (marked induction of indolamine
2,3-dioxygenase)
Microglial Function
Resting cells provide support and protect neurones. Growth
factors released by microglia. Presence of viral or other antigens
result in activation of microglia and migration towards the source
of antigents. Secrete substance that kill, superoxide, nitric
oxide, pro-inflammatory cytokines (TNF-alpha). Respond to degraded
neurones to attack and remove damaged neurones. Myelin fragments
activate microglia and result in them converting to a phagocytic or
macrophage-like state. Consume cellular debris from neurones that
have died.
Microglia and Cell Death
Differing views on the role played by microglia in
neurodegenerative disease. Cell culture studies show that certain
proteins produced by neurones during neurodegenerative diseases
e.g. amyloid, cause microglia to become activated and kill neurones
by the production of reactive oxygen species (e.g. peroxynitrate).
Activation of microglia is different in culture as compared to in a
brain. Some suggest that microglia do not play an active role in
killing otherwise healthy cells in the brain. Microglia respond to
damaged neurones by killing them Other viewed suggest that this
also does not occur and that microglia only become activated in
response to dead cells to remove debris.
Astrocytes
Out number Neurons 50:1
Protoplasmic Astrocyte: Gray Matter
Maintain blood brain barrier, interstitial environment Transport
processes for K+, glucose
Fibrous Astrocute: White Matter
Support, structure Form scar tissue
Processes
GFAP glial fibrillary acidic protein intermediate filament
Perivascular Feet (Foot Process, Vascular End-Feet) surround blood
vessels
Astrocyte Function 1:Pathway
During development astrocytes provide the pathways used by
neurones to migrate to their appropriate sites. Role in axonal
guidance (the ability of the axon of a neurone to connect to its
correct target Create boundaries or decision points for axonal
movement. Proteins involved in these axonal pathfinding included
CAMs, cadherins, integrins, selectins (more in later lectures).
Astrocyte Function 2: Support
Astrocyte Function 3(Growth, death)
Release large number of different factors Growth
factorsCytokines - Important for survival and development of
neurons During axonal damage, astrocytes proliferate around the
site of the damage. This could be to aid repair but in extreme
cases the astrocytes form a glial scar that can inhibit axonal
regeneration.
Astrocyte Function 4: Calcium Signalling
Gap junctions between astrocytes that allow them to communicate
rapidly using calcium. In culture calcium waves can be observed
sweeping through astrocytes very rapidly
During a calcium wave, the synaptic environment changes
dramatically. The astrocytic calcium wave reduces Ca2+ in the
cleft. Decreased [Ca2+] in the cleft inhibits further
neurotransmitter release, despite the arrival of action potentials.
Only with termination of the astrocytic calcium wave will Ca2+
return to its original level in the synaptic cleft allowing
neurotransmitter release at high levels. By simultaneously
regulating neurotransmission in all of the synapses an astrocyte
has enveloped, the astrocytic calcium wave may coordinate synapses
into synchronously firing groups. Thus, all of the synapses
enveloped or partially enveloped by an astrocyte may be within that
astrocyte's domain of synaptic influence. In effect, one group of
neurons could possibly influence another distant group of neurons
through strictly astrocytic pathways. The implications of this are
enormous; entire models of cognitive functioning could possibly be
infuenced by these astrocyte to neuron communications.-Filipodial
extensions..endfeet moving up neurotransmitter gradienthistory of
use increases probability of astrocytic control
Astrocyte Function 5(glutamate)
- clear released glutamate. - GLAST, GLT-1. important in
preventing excitotoxic death. Glutamate converted to glutamine and
returned to neurones.
Astrocyte Function 6: BBB
The BBB normally excludes circulating immune effector molecules
such as immunoglobulin and complement. Ediden (1972) reported that
MHC antigens were not expressed in brain. Minimal neutrophil
recruitment following excitotoxin-mediated neuronal degeneration.
Naive T cells are unable to cross the BBB.
Astrocyte Function 7: K+ and Glucose Transport
GLUT= glucose transportor
Immunological privilege
In most parts of the body allografts (transplanted tissue from a
donor) are rejected because of lack of immunological compatability
(MHCs). Allografts placed in the CNS do not reject Oligodendrocytes
transplanted into the CNS of some mice do not reject (Gumpel 1983).
Transplantation of embryonic nigral tissue ameliorates functional
deficiencies in Parkinson disease (Lindvall 1994).
Astrocyte Function 8(channels and receptors)
Ion channels, and neurotransmitter receptors- Express ion
channels for Ca2+ and K+- Important to maintain interstitial level
of ions- Express neurotransmitter receptors
Astrocyte Function 9(extracellular volume)
Determinant of the volume fraction of the extracellular space.
Astrocytic swelling has been shown to occur as a result of both
glutamate and adenosine receptor stimulation. Filopodial extension,
or outgrowth of membrane, can be induced in astrocytes by focal
application of glutamate. alters size and morphology altering
extracellular space. Synaptic function is sensitive to the
extracellular volume fraction. volume fraction decreases =
increased concentration of extracellular molecules Ie increases
effective concentrations of neurotransmitters astrocytes, through
modulation of their size, can influence the excitability of
neurons.
Astrocyte Function: ???
Possibilities for influencing neuronal excitability- Possible
influence of change in astrocyte membrane potential- Effects on
calcium concentration Research has shown that developing neurons in
culture do not achieve fully functional synapses until glia are
introduced though the mechanism of action for this is not known.
Regulation of Metals - can uptake metals which influence neuronal
activity
Cytokines
Produced by both astrocytes and microglia and by neuronsIn the
nervous system these protein can alter cell survival and
proliferation. either a pro-inflammitory or anti-inflammatory
response.
Cytokines can have different actions depending on: Their point
of release, The cells they act upon Concentration.
Include, interferons (IL), interleukins(IFN), tumor necrosis
factor (TNF)family, tranforming growth factor family (TGF),
chemokines, colony stimulating factors (CSF) variety of related
protein which can also act as growth factors such cilliary
neurotrophic factor (CNTF).
Structure of Cytokines
Molecular weight less than 30 kDa One of the hematopoietin
family, interferon family, tumor necrosis factor family or
chemokine family High degree of -helix structure Little or no
-sheet structure Share similar polypeptide fold
Cytokine Receptors
There are specific receptors for cytokines that can be activated
by a variety of cytokines. Microglia, astrocytes and
oligodendrocytes express receptors for many cytokines IL-1, IL-4,
IL-10, TNF-R1, TNF-R2 TGF-b, IFN receptors, gp130 and CNTR.
Microglia also express IL-6 receptor Gp130 can bind a variety of
cytokines including LIF and IL-6.
Three subfamilies:GM-CSF receptor subfamily, IL-6 receptor
subfamily, and IL-2 receptor subfamily
Signal transduction mediated by cytokine receptors
Cytokines Produced (neurones)
Stimulus Stresses Hypoxia, Axotomy, other damagesCytokine
FunctionM-CSFmicroglia activationchemokinesmicroglia
recruitment
Cytokines Produced (Astrocyte)
Stimulus Viruses, microglia, macrophage IL-1beta, TNF, TGF-beta
Cytokine FunctionIFNa/bAntiviral activityIL-6Inflammation, glial
activation, acute phase responseTGF-bDownregulation if
inflammation, neuroprotectionM-CSF, GM-CSFMicroglial proliferation,
activationChemokinesLeukocyte recruitment, glial activationCNTF,
LIFNeuroprotection
Cytokines Produced (Microglia)
Stimulus Damaged cell, Virus bacteria, Pathogens molecules,
Activated T cellsCytokine FunctionIL-1 TNFTissue breakdown/repair,
glial activationIL-6inflammation, glial activation, acute phase
responseTGF-bDownregulation if inflammation, neuroprotectiontissue
repairIL-10Downregulation if inflammation, neuroprotectionIL-12,
IL-15, IL-16Stimulates cell mediated immune
responseChemokinesLeukocyte recruitment, glial activation
Other Glial Types
Radial Glia - a transitory population of cells found during
development. Act as a scaffolding for neuronal development. Have
long projections that extend from the inner to the outer surface of
the cortex. Neuronal progenitor cells migrate along them during
development. Can develop into other glial types or even neurones.
Bergmann Glia, radial astrocytes of the cerebellum. Lie in the
Purkinje cell layer and have long projections that extend into the
molecular layer. Each Bergmann glia ensheaths 2000-6000 Purkinje
cell synapses. Mller Glia, radial glia of the retina, with
microglia like activity. Have projections that contact every layer
of the retina.
Radial glia
Embryonic scaffold throughout CNS Guides for radial migration of
neurons Produce matrix and adhesion proteins