What do you notice?

Thomas Deerinck, NCIMS

Colors, textures, first impressions?

 Glial cells of the central nervous system
can outnumber neurons by a dynamic (changing) ratio

ventricle
and cerebral spinal fluid (CSF)
ependymal cells

astrocytes
neurons

oligodendrocytes microglia

capillaries
Ependymal Cells:
choroid plexus: epithelium lining the ventricles and central canal of the spinal cord that is composed of modified
ependymal cells.

Steve Gschmeissner
Neuroscience 4th Edition, Bear, Connors, Paradiso
Ependymal Cells:
choroid plexus: epithelium lining the ventricles and central canal of the spinal cord that is composed of modified
ependymal cells.

The choroid plexus produces cerebrospinal

fluid (CSF) and its tight junctions form a
blood-CSF barrier

Ventricle

Le et al., Int. J. Nanomed., 2014

Ependymal Cells:
choroid plexus: epithelium lining the ventricles and central canal of the spinal cord that is composed of modified
ependymal cells.

Cerebrospinal fluid circulates nutrients

(e.g. glucose) and chemicals (e.g. ions)
filtered from the blood and removes
waste products. It also cushions the
brain within the skull.
Microglia:
Defenders and sculptors neurons (red), microglia (green)

Steve Gschmeissner Dailey Lab, University of Iowa

Microglia:
Defenders and sculptors
phagocytosis: process by which a cell ingests other cells or particles

Microglia become activated in response to injury

Resting Microglia Active Microglia

Grzegorz Wicher, Uppsala University

Microglia:
Defenders and sculptors
phagocytosis: process by which a cell ingests other cells or particles

Microglia (green)
Nuclei of dead cells (red)

Time-lapse sequence of a microglia cell picking

up a dead cell nucleus “on the fly” Petersen and Daily, Glia, 2004
Microglia:
Defenders and sculptors
In response to injury, microglia surround the injury site, produce immune response molecules, and engulf damaged
tissue.

Microglia (green)
Nuclei of dead cells (red)

An activated microglia extends a branch toward

an injured neuron, contacts it, and engulfs it
Eyo & Dailey, J. Neuroimmune Pharmacol, 2013
Microglia:
Defenders and sculptors
In response to injury, microglia surround the injury site, produce immune response molecules, and engulf damaged
tissue.

Resting Microglia Laser-induced ablation Local injection of ATP

note: they are still quite active!
Damaged neurons can release high amounts of ATP. ATP is sufficient to instigate the microglia response.
“A factor is necessary if it is an absolute requirement for the effect, and it is sufficient if it can produce the effect in
isolation (i.e., without the action of any other factors).” Coleman et al., Biochem Mol. Bio. Edu., 2015
Microglia:
Defenders and sculptors
phagocytosis: process by which a cell ingests other cells or particles

note: you are not required to know the

molecules that signal phagocytosis

Of particular importance, microglia are

signaled to aid in the following tasks:

1. Removal of synapses and neurites

2. Removal of entire (stressed or
damaged) neurons

Synapse and neurite removal can help

neurons flexibly adapt to changing
circumstances both during and after
development.

Brown and Neher, Nature Rev. Neuro., 2014

Oligodendrocytes:
myelin sheath: spiral wrapping and compression of the oligodendrocyte (in the CNS) plasma membrane around the
axon that provides both electrical insulation (greatly enhancing the speed of electrical signals) and support.

myelin sheath

note: myelin sheath is formed by Schwann cells in the PNS.

Oligodendrocytes:
myelin sheath: spiral wrapping and compression of the oligodendrocyte (in the CNS) plasma membrane around the
axon that provides both electrical insulation and support.

One oligodendrocyte can encircle the axons from

multiple neurons

In the peripheral nervous system, a Schwann cell

encircles only one axon.

University of Toronto
Astrocytes:

Nedergaard, University of Rochester Benediktsson et al., Journal of Neuroscience Methods, 2005

astrocyte (green), neurons (blue), and blood vessel (red)

Astrocytes:
blood-brain barrier: barrier formed by endothelial cells, pericytes, and astrocytes that restricts the passage of
substances (e.g. antibiotics) from the bloodstream to the brain.

Select substances cross the blood brain barrier via

passive diffusion (e.g. fat-soluble alcohol, nicotine,
and caffeine) or active transport (e.g. glucose) across
the epithelium.

Astrocyte end-feet encircle the endothelial cells, and

their interactions influence blood-brain barrier
induction, maintenance, and short-term permeability.

Tomabene and Brodin, J. Pharm. Sciences, 2016

The blood-brain barrier restricts the passage of substances from the
bloodstream to the brain. What are some advantages and
disadvantages of the blood brain barrier? What happens if it is
damaged?

Learning outcome: Describe the composition of the blood-CSF and

blood-brain barrier and identify positive and negative consequences of
restricting the passage of substances from the bloodstream to the
brain.
Astrocytes:
How is the blood-brain barrier related to
the blood-CSF barrier?

D’Agata et al., Molecules, 2018

Astrocytes:
the tripartite synapse: a presynaptic neuron, a postsynaptic neuron, and the surrounding astrocytes that
surround a synapse

Eroglu and Barres, Nature, 2010

Structural features of astrocytes are thought to influence synaptic transmission by 1) segregating neighboring
synapses by isolation of chemical release and 2) altering the geometry of space between brain cells.
Astrocytes:
the tripartite synapse: a presynaptic neuron, a postsynaptic neuron, and the surrounding astrocytes that
surround a synapse
One astrocyte can contact ~100,000 synapses.

Parea et al., Trends Neuro., 2009

3D reconstruction of a single astrocyte process (blue) interdigitating among

four dendrites (gold, yellow, red and purple)
Astrocytes:
the tripartite synapse: a presynaptic neuron, a postsynaptic neuron, and the surrounding astrocytes that
surround a synapse

1) Astrocytes exhibit elevations in Ca2+ in response

to neurotransmitter release. This is mediated by
neurotransmitter receptors on the astrocytes.

1) Ca2+ increases occur in spatially restricted areas

called microdomains, which can eventually
propagate to other regions of the astrocyte.

2) Astrocytes can release gliotransmitters that can

influence synaptic transmission. (e.g. glutamate,
GABA, ATP)

Parea et al., Trends Neuro., 2009

Astrocytes:
Astrocytes can release factors that can influence the development or modification of synapses (including
removal by microglia). They can also influence synaptic transmission at synapses without enacting structural
changes.

Astrocytes can mediate:

1) The development of new,

silent synapses (left)

2) An increase in the probability

of presynaptic
neurotransmitter release
(middle)

3) An increase in postsynaptic
glutamate receptors (right)

e.g. thrombospondins e.g. cholesterol

Eroglu and Barres, Nature, 2010
Astrocytes:
phagocytosis: process by which a cell ingests other cells or particles

Astrocytes also play indirect and direct roles in phagocytosis.

Indirect: astrocytes signal the expression of proteins that Direct: astrocytes recognize “eat-me” signals at silent
are recognized by microglia, and microglia engulf the synapses
synapse.
note: you do not need to know the specific molecules

Chung et al., Cold Spring Harbor Pers. Biol., 2015

Glia Signaling

In addition to extracellular signaling, astrocytes and oligodendrocytes can communicate via gap junctions.

synapseweb.clm.utexas.edu/astrocytes

Increases in calcium can propagate across astrocytes.

In this manner, astrocytes can communicate with other astrocytes.
Astrocytes communicate with calcium waves

Fields, Nature, 2013

Secondary injury in traumatic brain injury
note: you do not need to know all these pathways

Through a number of pathways, glia can contribute to secondary injury. These pathways include:
1) The release of pro-inflammatory cytokines (proliferating the response)
2) The release of glutamate (which can result in excitotoxicity, killing neurons)
Microglia and inflammation in Alzheimer’s disease
Microglia are also activated by Aβ (accumulates in Alzheimer’s disease), which can contribute to neuron loss

Block, BMC Neuro, 2008

Neural Disorders involving Glia:

Microglia ingesting oligodendrocytes

Multiple sclerosis (MS) is a chronic inflammatory and
neurodegenerative disease of the central nervous system
(CNS) characterized by focal lesions of inflammation,
axonal loss, gliosis (including the activation of microglia),
and demyelination that affect the white and gray matter

Demyelination causes electrical signals to slow or stop.

John Zajicek
What are some ways in which glia respond to neuronal activity, silence,
or injury? How do they know how to respond?

Learning outcome: Apply knowledge of the manner in which glia send

and receive signals in order to anticipate their responses to neuronal
activity, silence, or injury.
Summary:
• Glia have a number of roles in providing an important support structure for the
brain: the blood-CSF barrier, the blood-brain barrier, the tripartite synapse.
• Glia also release a number of substances that can dramatically influence the
manner in which neurons communicate and adapt to changing circumstances.
• Although many of these roles support neuron communication, glia also have the
ability to communicate signals.