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Characteristics of
brain glial cells
Mike Zuurman Med. Fysiologie
Different brain cell types
• Glial material was first described by Rudolf
Virchow (1846). ”..substance that lies between the
proper nervous parts, holds them together and gives
the whole its form. ..its differences to other
connective tissue has induced me to give it a new name,
that of neuro glia.”
• In 1891 the cellular structure of the brain
was recognized: H.W.G von Waldeyer`s
created the term neurons and C. Golgi
discoverd and described astrocytes and
suggested a nutritive role of neuroglia
• In 1921 R.del Hortega distinguished 2 cells
in brain which he named microglia and
oligodendrocytes
• C.L Schleich (1894) suggested active and
dynamic roles for glial cells in the whole
specturm of brain functions
Glial cell markers
Cell type
Marker
Oligodendrocytes Myelin basic
protein (MBP)
Galactocerebroside
(GC)
Microglia
ED-1, OX-42,
F40/80, MAC-1
Astrocytes
Glial fibrillary
acidic protein
(GFAP),
Glutamate
astrocytic
transporter
(GLAST)
Developmental origin of glial cells
neuroectoderm
Neuroectoderm
Mesoderm
Bone Marrow
Neuroepithelial stem cells from
developing ventricular zones
?
Microglia
Oligodendrocytes
Astrocytes
Neurons
There are 10 times as much astrocytes in human brain as there are neurons
50% of the brain mass
There are as much microglia or oligodendrocytes in human brain as neurons
Glial cell lineages
glial cells
glial progenitor cells
neuronal progenitor cells
?
neurons
stem cells
neuronal ventricular zone
oligodendrocytes
O2A lineage
O2A progenitor cell
RAN-2 A2B5 +
+ growth
factors and ECM
GFAP +
A2B5 +
?
T1A lineage
type 1 astrocyte
T1A precursor
RAN-2 +
?
A2B5 ?
type 2 astrocyte
GC +
GFAP A2B5 -
radial glial cells
GFAP +
RAN-2 +
A2B5 -
?
neurons GFAP -
A2B5
GFAP
GC
radial glial cells in the
developing CNS
survace of the developing cortex
ventricular zone
time
Radial glia: multi-purpose
cells for CNS development
T1A lineage
type 1 astrocyte
T1A precursor
?
radial glial cells
?
neurons
mitosis
+
Functions of oligodendrocytes in
the brain
•
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synthesize, assemble and maintain myelin
form myelin sheath which are wrapped around axons
Oligodendrocytes and formation of myelin
origin of microglial cells
Invasion of the brain by monocytes and development of microglia
ED 18
Invasion by
monocytes
birth
PD3-4
PD 5
PD 22
Formation
of the BBB
Beginn of
ramification
End of
ramification
Functions of microglia in the
brain
resting (ramified) microglia
fully activated (phagocytic) microglia
intermediate states
•
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Major immuncompetent cell of the brain
MHCII expression and antigen presentation
beneficial (production of neurotrophins) and
detrimental (synaptic stripping, phagocytose)
effects on neurons
different types of astrocytes
type 2 astrocytes
GFAP +
A2B5 -
type 1 astrocytes
GFAP +
A2B5 +
Functions of astrocytes in the
brain
•
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formation of growth tracts to guide the migration of
neurons during early devlopment
production of trophic factors for neurons before they
make connections with postsynaptic cells
participate in the immune response of the brain
scar tissue formation following neuronal loss
storage of glycogen as an energy reserve in the brain
uptake and release of neuroactive compounds
buffering of the extracellular ion homeostasis (spatial
buffering of K+ ions)
participate in the formation of the blood brain barrier
metabolic coupling between astrocytes and neurons
neuron-glia and glia-neuron communication
calcium: metabolism and its
role in neuronal death
Mechanism of excitotoxicity
Mg++
Na+
Na+
Non-NMDA
NMDA
K+, Ca++
K+, Ca++
Ca++
Neuronal death
Metabolic coupling between
astrocytes and neurons
from Tsacopoulos and Magistretti (1996)
Termination of glutamate signaling and a subsequent
activation of glycolysis
in cases of energy failiure (ischemia) astrocytes are the
main source for the high extracellular glutamate concentrations
Glutamate and intracellular calcium
signaling: the basis for glia-glia,
neurone-glia and glia-neurone
communication?
•
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glutamate is the major
exitatory neurotransmitter
in brain
ionotropic receptors and
metabotropic receptors,
which are expressed by
neurons and astrocytes
stimulation of glutamate
receptors may induce
calcium signaling
over stimulation with
glutamate leads to neuronal
death, glutamate induced
neurotoxicity is the major
damage in ischemia
•
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calcium is important
intracellular messenger and
has a vast array of
different functions in the
cell
calcium signals can be
distinguished in singel
calcium spikes and calcium
waves
calcium waves can occur
intracellular as well as
intercellular and they can
occur in nearly all cells
the function of calcium
waves are still unkown
Features of astrocytes in the
brain
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Allmost all receptors found on neurones were
expressed by astrocytes as well (neurotransmitters,
neuropeptides, growth factors, cytokines…)
they express a great variety of ion channels (voltage
gated and transmitter gated)
transport systems for ions, neurotransmitters…….
formation of “networks” via gap junctions
size of astrocytic networks is brain region dependent
Calcium signaling in cultured
astrocytes
Calcium signals in astrocytes are (partly) stimulus specific, reproducible,
complex in terms of strengh, velocity (10-30 um/s) and spacial aspects
Calcium signals observed in various
brain cell preparations
stimulation of neurones causes
calcium signals in astrocytes in culture, (1992)
in vivo like systems (1996)
Calcium waves
spread through
astrocytes
in culture, (1990)
in vivo like
systems (1995)
Questions?
what is the neuron-astrocyte
signal?
how does the calcium signal spread
through the astrocyte network?
what is the astrocyte-neurone
signal?
what does it all mean, are there
physiological effects, is this real
communication between neurones
and astrocytes?
Astrocytic calcium
signaling induces
calcium signals
in neurones (1994)
Neuron-astrocyte
signaling
Hippocampal slices
neurons in Schaffer collaterals
astrocytic intracellular calcium in stratum radiatum
low frequency
no effect
high frequency
Calcium transients in astrocytes
Transmitter:
glutamate
Astrocytic calcium waves are dependent on neuronal activity
Porter and McCarthy, 1996; Pasti et al., 1997
Astrocyte-astrocyte
signaling
Astrocyte-astrocyte
signaling
ATP
Cotrina et al.,
1998, 2000
Synaptic neuronal activity controls the
development of astrocytic networks
(Rouach et al., 2000)
astrocyte - neuron
signaling
Glutamate
- Parpura et al., 1994
and several other papers
Gap-junctions
- Nedergaard, 1994
- gap-junctions between neurons and astrocytes
in culture (Froes et al., 1999)
- gap-junctions between neurons and astrocytes
in locus ceruleus (Alvarez-Maubecin et al., 2000)
Astrocytes may control
synaptic plasticity
Araque et al.,
- astrocytic glutamate modulates the magnitude of action potential-evoked
transmitter release (1998a)
- as well as the the probability of transmitter release in unstimulated synapses
(1998b)
- astrocytes mediate potentiation
of inhibitory synaptic transmission
in hippocampal slices
(Kang et al., 1998)
- astrocytic modulation of neuronal
activity in the retina
(Newman and Zahs, 1998)
Astrocytes, integrators
of synaptic activity?
Two principles of signal transmission in
brain:
Wiring against Volume transmission
(Zoli and Agnati, 1985)
•
Single “transmission
channel” made by cellular
structures and with a
region of discontinuity not
larger than a synaptic cleft
•
Diffusion of a cell source
of chemical signals in the
extracellular fluid for a
distance larger than the
synaptic cleft
•
Hardware for WT neurons
and astrocytes, synapses
and calcium signaling
•
NO, dopamine, adenosine
neuropeptides are known to
diffuse for more than 1mm
in brain
neuromodulators differ
from neurotransmitters in
that their effects are
generally more global and
longer lasting than the
effects of the latter
(F. Bloom, 1988)
Hardware for VT
extracellular fluid in the
interstitial volume fraction
(20% of the brain volume)
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Swelling of astrocytes may influence
“volume wiring” in the brain
open synapse
closed synapse
This has not been shown so far, it is a theory. But it is
pretty clear that astrocytic volume changes occur in invivo like preparations and that the swelling and
shrinkage of astrocytes is controlled by intracellular
calcium signaling
neuron : astrocyte
ratio
leech
10:1
rodents
1:1
human
1:10
Conclusions
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Like neurons are glial cells derived from ventricular
zone stem cells
oligodendrocytes built up the myelin sheath around
axons
miroglia are the major immunocompetent cell of the
CNS
astrocytes are involved in CNS pattern formation
astrocytes and neurons are metabolically coupled
glutamate and intra- inter-cellular calcium signals
between astrocytes and neurons are capable of
modulating synaptic activity
“….one now begins to feel more comfortable with the
concept that the majority of cells in the CNS are no
longer “passive partners” to neurons” A. Vernadakis
(1996)