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 basicprotein (MBP)Galactocerebroside(GC)

Microglia ED-1, OX-42,F40/80, MAC-1

Astrocytes Glial fibrillaryacidic protein(GFAP),Glutamateastrocytictransporter(GLAST)

NeuronsMicroglia AstrocytesOligodendrocytes

Neuroectoderm

Bone Marrow

There are 10 times as much astrocytes in human brain as there are neurons50% of the brain massThere are as much microglia or oligodendrocytes in human brain as neurons

Neuroepithelial stem cells from developing ventricular zones

?

Developmental origin of glial cells

Mesoderm

neuroectoderm

Glial cell lineages

neuronal progenitor cellsglial progenitor cells

neurons

glial cells?

neuronal ventricular zone

stem cells

O2A lineage

O2A progenitor celltype 2 astrocyte

oligodendrocytes

GFAP +A2B5 +

GC +GFAP -A2B5 -

T1A lineage

T1A precursor type 1 astrocyte

radial glial cells

?

neurons

??

?

RAN-2 -A2B5 +

RAN-2 +A2B5 -

GFAP -

GFAP +RAN-2 +A2B5 -

+ growthfactors and ECM

A2B5 GC

GFAP

radial glial cells in the developing CNS

time

ventricular zone

survace of the developing cortex

Radial glia: multi-purpose cells for CNS development

T1A lineage

T1A precursor type 1 astrocyte

radial glial cells

neurons

??

+mitosis

Functions of oligodendrocytes in the brain

• 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 birth PD3-4 PD 5 PD 22

Invasion by monocytes

Formation of the BBB

Beginn of ramification

End of ramification

Functions of microglia in the brain

• Major immuncompetent cell of the brain• MHCII expression and antigen presentation• beneficial (production of neurotrophins) and

detrimental (synaptic stripping, phagocytose) effects on neurons

resting (ramified) microgliafully activated (phagocytic) microglia

intermediate states

different types of astrocytes

type 2 astrocytes type 1 astrocytes

GFAP +A2B5 -

GFAP +A2B5 +

Functions of astrocytes in the brain

• 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

K+, Ca++

Na+

Non-NMDA

K+, Ca++

Mg++

NMDA

Na+

Ca++

Neuronal death

Mechanism of excitotoxicity

Metabolic coupling between astrocytes and neurons

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

from Tsacopoulos and Magistretti (1996)

Glutamate and intracellular calcium signaling: the basis for glia-glia, neurone-glia and glia-neurone

communication?

• 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

• 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

• 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

Features of astrocytes in the brain

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

Questions?

what is the neuron-astrocytesignal?

how does the calcium signal spread through the astrocyte network?

what is the astrocyte-neurone signal?

what does it all mean, are therephysiological effects, is this real communication between neurones and astrocytes?

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)

Astrocytic calciumsignaling induces calcium signals in neurones (1994)

Neuron-astrocyte signaling

Hippocampal slicesneurons in Schaffer collateralsastrocytic intracellular calcium in stratum radiatum

high frequency Calcium transients in astrocytes

low frequency no effect

Transmitter: glutamate

Astrocytic calcium waves are dependent on neuronal activityPorter and McCarthy, 1996; Pasti et al., 1997

Astrocyte-astrocyte signaling

Astrocyte-astrocyte signaling

ATPCotrina et al., 1998, 2000

Synaptic neuronal activity controls the development of astrocytic networks(Rouach et al., 2000)

astrocyte - neuron signaling

Glutamate- Parpura et al., 1994and 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)

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 may control synaptic plasticity

- 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

• Hardware for WT neurons and astrocytes, synapses and calcium signaling

• Diffusion of a cell source of chemical signals in the extracellular fluid for a distance larger than the synaptic cleft

• 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)

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 in-vivo like preparations and that the swelling and shrinkage of astrocytes is controlled by intracellular calcium signaling

leech rodents human10:1 1:1 1:10

neuron : astrocyte ratio

Conclusions

• 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)