Lesson (1)

The cellular organization

of the nervous system
(neuroglia)

The neuroglia: structure and functions

There is a debate on their actual number (formerly 10 times):
now 2-3 times the number of the neurons

5 main types:
-Astrocytes
MACROGLIA -Ependimal cells
-Oligodendrocytes
-Schwann cells
-Microglia
Functions:
-Filter (Blood-Brain Barrier)
-Physical support
-Protection (sequestration of ion or neurotransmitters in excess;
resident immune system)
-Trophic and metabolic support
-Signal transduction (transcytosis, myelin formation)
-Regeneration and degeneration/scar formation (neural stem cells)

What are glia?

Neuroglia=nerve glue (Virchow, 1859)
Glia as cells: S. Ramon y Cajal, P. del Rio-Hortega, 1900-1920

A spatial view of neuroglial Cells of CNS

THE NEUROGLIA:
some FUNCTIONs

Astrocytes & Ependimal cells: Blood brain

barrier, support, trophic, signalling, support, homeostasis

Oligodendrocytes
Support & myelin, signalling
Schwann Cells
Microglia: resident immune system

Astrocyte/capillary
interactions: foot process

Two types of astrocytes

-Protoplasmic (pedunculated) in the grey matter
- fibrous in the white matter
Pedunculated astrocytes

Fibrous astrocyte in the cerebellum white matter

Astrocytes (astroglia) star-cells

Most numerous cell type in brain
Constitute ~30-50% of brain volume
NORMAL FUNCTIONS
Developmental: Migrational and Axon
guidance of neurons
Trophic support of neurons (growth
factors)
Homeostasis of neuronal
microenvironment
Ionic
Metabolic
Neurotransmitter uptake
Blood-Brain barrier: induction and
maintenance
Synaptogenesis and synaptic remodeling

Astrocytes
Astrocytes contact virtually every cell
component in brain
Other astrocytes (gap junctions)
Ependymal cells
Neurons (somas, processes, synapses)
Oligodendroglia
Capillary endothelial cells

Astrocytes
Trophic function:
produce growth factors/neurotrophic factors (NGF,
BDNF, GDNF, CNTF, FGFs), especially in
development and regenerative responses to injury
Buffer extracellular space to maintain
homeostasis for neuronal function:
K+ spatial buffering
Protect neurons from excitoxicity: active glutamate
uptake/conversion to glutamine (cycled back to
neurons)

Astrocytes communicate with each other,

other glia, and neurons via intercellular calcium waves
mediated by GAPGAP-junctions and extracellular signals

Calcium Waves in Retinal Glial Cells

Eric A. Newman and Kathleen R. Zahs
Science 1997 February 7; 275: 844-847.

Glia work in unsuspected ways: synaptic

depression after glia contacts synapses

AChBP as a
nAChR decoy

Nature 411, 261 - 268 (2001)

How did they figure this out?

(or, what does it take to get a paper in Nature?)

Observation:
Cultured neurons formed Ach synapses
When glia were allowed to contact synapses, synaptic
depression was observed

Question:
How do the glia sense and respond to the Ach to modulate
transmission ?

Finding:
It senses Ach by AchBP (identified by Bungarotoxin
purification scheme, partial AA sequence)

Response:
Glia have nAChR, which senses increased Ach and induces
release of AChBP from glia into the cleft, suppressing
transmission (negative feedback).

Who are the stem cells of the adult brain?

astrocytes vs. ependymal cells
The subventricular zone

Ependymal cells
June 15, 1999

Astrocytes

Brain Stem Cell Is Discovered, Twice

By NICHOLAS WADE
Dr Arturo Alvarez-Buylla and Dr Jonas Frisen report
discovering site in brain of elusive neural stem cell,
founding cell from which perhaps whole brain
develops, but each scientist has a different site in
mind; Frisen contends that neural stem cells are cells
that line ventricles, while Buylla contends neural
stem are the star-shaped cells called astrocytes that
lie one layer in from ventricle lining; experts say
their contradictory findings may yet be reconcilable

Johansson et al., "Identification of a neural stem cell in the adult mammalian central nervous system," Cell, 96:25-34, 1999.
Doetsch et al., "Subventricular zone astrocytes are neural stem cells in the adult mammalian brain," Cell, 97:703-16, 1999.

Astrocytes control synapse formation

Control of Synapse Number by Glia

Erik M. Ullian, Stephanie K. Sapperstein,
Karen S. Christopherson, and Ben A.
Barres
Science 2001 January 26; 291: 657-661.

Astrocytes in disease: gliosis

Astrocytosis/gliosis
= response of astrocytes
to many forms of injury:
trauma, inflammation, MS,
infection,
neurodegeneration
MS plaque: GFAP

Astrocytes-gliosis
Classical description of gliosis is:
hypertrophy,
+/- proliferation,
Prominent expression of intermediate filaments: Glial filaments:
- Glial Fibrillary Acidic Protein (discovered as a major component of
Multiple Sclerosis White Matter Plaques)
- Also, vimentin, nestin

Reality: there must be many distinct forms of

astrocyte activation; hundreds or thousands of
distinct changes in gene expression

More reactive astrocytes

(gliosis)

BBB=endothelial tight
junctions

Basment membrane

Endothelial

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Ependymal cells
Line ventricles of brain and spinal cord canal
Ciliated, columnar epithelium, with cilia and
adherens junctions; but express glial markers
May extend cytoplasmic processes into brain
parenchyma
Recent controversy as to whether Ependymal
cells (versus subependymal astrocytes) are
adult neural stem cells

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Ependymal cells

Chroiod plexus

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Oligodendroglia (CNS)

Oligodendroglia (CNS)
few-branch glia
Discovered by del Rio-Hortega, using metallic impregnation
techniques in 1921
one oligo myelinates many CNS axons
CNS myelinators (white matter)
Target of autoimmune attack in MS

Specific oligodendrocyte myelin proteins:

PLP
DM20
MBP

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Ultrastructure of white matter

Oligodendroglia
1 glial cell forms myelin around many axons

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Schwann Cell (PNS)

Schwann Cell

Theodore Schwann (19th cent. German anatomist; a key founder of

cell theory)
Each Schwann cell wraps a portion of a single peripheral axon

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Myelinated perypheral axons

Myelin 1
Myelin acts as an insulator for vertebrate
nerve cells
Cellular structure - myelin is composed of
alternating layers of protein and lipid (20%
protein and 80 % lipid (looks white)

Very little cytoplasm between layers

Myelin represents a major vertebrate feature
Not a major factor in invertebrates nervous systems
Major advantages
faster conduction (10x)
smaller sized neurons (10x)

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Myelin 2
Oligodendrocytes in CNS and Schwann cells in PNS
Oligodendrocytes in CNS myelinate several fibers
myelination spirals inward with new layers pushed under the older
ones

In CNS - no neurilemma or endoneurium

In PNS, hundreds of layers wrap axon
the outermost coil is schwann cell (neurilemma)
covered by basal lamina and endoneurium

Gaps between myelin segments = nodes of Ranvier

Initial segment (area before 1st schwann cell) and
axon hillock form trigger zone where signals begin

Myelin Sheath

Note: Node of Ranvier between Schwann cells

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Myelination in PNS

Myelination begins during fetal development, but

proceeds most rapidly in infancy.

Unmyelinated Axons of PNS

Schwann cells hold small nerve fibers in

grooves on their surface with only one
membrane wrapping

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Myelination in CNS

Speed of Nerve Signal

Diameter of fiber and presence of myelin
large fibers have more surface area for signals

Speeds
small, unmyelinated fibers = 0.5 - 2.0 m/sec
small, myelinated fibers = 3 - 15.0 m/sec
large, myelinated fibers = up to 120 m/sec

Functions
slow signals supply the stomach and dilate pupil
fast signals supply skeletal muscles and transport sensory
signals for vision and balance

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Impulse Conduction - Unmyelinated Fibers

Saltatory Conduction - Myelinated Fibers

Voltage-gated channels needed for APs
fewer than 25 per m2 in myelin-covered regions
up to 12,000 per m2 in nodes of Ranvier

Fast Na+ diffusion occurs between nodes

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Peripheral Nerve (Fascicle)

Perineurium

Endoneurium

Myelinated axons

Peripheral nerve

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Neuropathological note
Tumors of the nervous system are largely
Glial tumors:
Peripheral: Schwannoma, Neurofibroma
Central:
astrocytomas (includes benign pilocytic astrocytic
and most common and most malignant:
glioblastoma multiforme)
Oligodendrogliomas
ependymomas

Multiple Sclerosis is an autoimmune

attack on white matter

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Major proteins found in Myelin

P0 (protein zero) intraperiod line formation
a glycoprotein only in myelin-forming Schwann cells (50%)
similar to CAMs, but bifunctional (in PNS)

proteolipid protein (PLP) intraperiod line formation

only in Oligodendrocytes (50%) (in CNS)

myelin basic protein (MBP)

expressed in both, involved in compaction
very antigenic, can be used to induce experimental multiple
scelerosis, (T-lymphocyte inv. of CNS and PNS
shiverer in mice

NCAM
Cellular adhesion

How these proteins work together

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Schwann Cells and Peripheral

Neuropathies
Schwann cells also perform trophic functions
(NGF production in regeneration).
Myelin proteins
Schwann cells (PNS): P0, PMP22
CMT1A=duplication of PMP22
HNPP=deletion of PMP22 (surprisingly, deletion causes
milder phenotype than CMT1A(duplication)

Radial glia
Embryonic scaffold throughout CNS
Guides for radial migration of neurons
Produce matrix and adhesion proteins

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Radial glia
Adult: radial glia persist in cerebellum
(Bergmann glia) and in retina (Muller cells)

GFAP

Gliogenesis
Note the absence
of microglia from
this family tree!

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Microglia: OX-42

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Microglia (as opposed to

Macroglia=astrocytes, oligos)
Most like tissue macrophages elsewhere in body; not
of neuroectodermal origin, like all macroglia
Chief mediators of immune responses in brain
CNS is not completely isolated from immune
reactions
Microglia derive from marrow monocyte lineage
Have phenotypic markers similar to tissue
macrophages:
CD68, HAM-56, IL-1alpha,beta, class II MHC, OX-42

Microglia
Most roles for microglia in context of CNS pathology;
little known yet about normal functions. Examples of
possible normal function are developmental:
phagocytosis of apoptotic neurons; secretion of factors
Activated microglia can produce and secrete cytokines
capable of activating astrocytes: e.g. IL-1; some think
microglia are the primary sensors of CNS damage.
Some say that they have no function in the healthy
adult brain: They dont form a network with intercellular
junctions, as do neurons and astrocytes
LIKE BODYGUARDS: THEY JUST SIT THERE WAITING FOR
AN INSULT

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Microgliogenesis

How do we know this is true?

Microglial activation

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Microglia

Blood-brain Barrier

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