Lecture 23- The Glial Brain

Question 1

What are the types of glial in the brain?

Answer 1

-Astrocytes: Eg Bergmann glia, Muller cells (types of astrocytes in the retina) -Oligodendrocytes -Schwann cells -Ependymal cells -Microglia (immune cells, not like other glia)

Question 2

What is the comparison in number of neurons and glia in the brain?

Answer 2

-glia outnumber neurons

Question 3

Where do glia occur?

Answer 3

-surround synapses but are dynamic

Question 4

Do glia exist in territories? What does that mean?

Answer 4

-yes -astrocytes exist in territories, occupy an area and take care of a few cells, these territories can change in disease

Question 5

Are glial at all synapses?

Answer 5

-Glial cell ensheath most synapses.

Question 6

What are the 4 conventional “passive” functions of glia?

Answer 6

1.Uptake and degradation of NTs: Glutamate and GABA (important for synaptic function, need to remove the NT otherwise the cell will continue to fire) 2. Potassium siphoning (remove potassium otherwise cell would die) 3. Energy metabolism (shuffle energy metabolites to the neurons= as neurons are far away from energy supply) 4. Maintenance of the Blood-brain barrier

Question 7

How are glia involved in Glutamate recycling?

Answer 7

• pink= glutamergic neuron
• glutamate released, does its job on postsynaptic
• GLAST= glutamate transporter on the glial cell, remove glutamate from the synaptic cleft
• glutamate is toxic, and is converted to glutamine in the glial cell and this is then sent back to neurons where glutamate is reformed
• extremely important for health of neurons in CNS

Question 8

How are glia involved in GABA recycling?

Answer 8

• GABA is shunted into Krebs cycle in the glial cells, important for creating ATP in the CNS
• 20% of all energy metabolism is created this way= from GABA in glial cells
• glutamine is also recycled to make glutamate and from that into GABA

Question 9

What happens when the GABA and glutamate recycling breaks down?

Answer 9

• Glial cells express Glutamate transporters.
• When transporters are inhibited, cells are more depolarized.
• when the line downwards= is more depolarized
• PDC= blocks the ability of glial cells to take up glutamate
• now the neuron has a massive response
• cell is massively depolarized as the glutamate is not taken away, it is also depolarized for much longer
• without the uptake of glutamate the cell will eventually die

Question 10

What is the role of glia in potassium siphoning?

Answer 10

• Potassium is found in high concentration during depolarization.
• Glial cells express inwardly rectifying potassium channels (eg Kir4.1, Kir2.1)
• Potassium is siphoned from areas of high potassium concentration to the vasculature -When a neuron depolarizes then high level of potassium is outside the cell
• you have to remove it
• if don’t remove it then neurons will be continually depolarized
• glial cells have potassium channels that will take up the potassium and thrown into blood vessels -if this doesn’t happen then very detrimental, swelling etc.
• crucially important fro health of the brain

Question 11

What is the role of glia in neuron energy metabolism?

Answer 11

-Glial cells wrap around blood vessels - Take up glucose. - Transport lactate to neuron -lactate is the metabolite that provides energy for neurons -important for neuron survival

Question 12

Are glia excitable cells?

Answer 12

-yes -glia are not just glue, they are excitable -initiated by neurotransmitters such as ATP, glutamate -Glial cells express receptors to a number of different neurotransmitters. -respond by changes in intracellular calcium (not APs) -this is how they regulate neural activity -calcium change in one glial cells creates increase in other glial cells -it is a way of glial cells to communicate with each other -the calcium signal is elicited by = trauma, spontaneous, inflammatory mediators (ATP etc.)

Question 13

What is a calcium wave?

Answer 13

• Glia have spontaneous waves. -calcium levels rise in the cell and pass it onto neighbouring cells

Question 14

What is the mechanism of glia communication?

Answer 14

-Glial cells contain synaptic vesicles and show exocytosis. -if have increase in intracellular calcium then release of vesicles -they are very like neurons -there are vesicles in astrocytes, have synaptic vesicles, which are released when calcium signal passes -the vesicles are being released and turned over, work very like neurons

Question 15

What do glial cells release?

Answer 15

-2 compunds -glutamate and ATP -the calcium waves are very important, involved in release of vesicles -gliotransmitter= neurotransmitter but in glia -Via release of gliotransmitters such as glutamate, ATP -Movie shows release of Glutamate from glial cell when stimulated by a calcium wave.

Question 16

What are the 2 purposes of what the calcium is doing? (number 1)

Answer 16

-changing neurons and changing blood vessels -1st purpose= can change neurons in its territory, neurons are hyperpolarized -modulation of neuronal activity -release of ATP= hyperpolarized neurons= ATP is broken down into adenosine that inhibits the neurons -directly changing the coltage of the neuron -active function of a glial cells -Neurons are inhibited by calcium wave. - Mechanism involves release of ATP from glia

Question 17

What is the 2nd purpose of what the calcium wave is doing?

Answer 17

2nd purpose of calcium wave: -there is no sympathetic innervation of blood vessels so astrocytes affect the amount of blood going to regions of the brain -Astrocytes surround blood vessels -Results of glial communication: Regulation of vascular calibre

Question 18

How do astrocytes affect vascular tone?

Answer 18

-Astrocytes regulate vascular tone. -Calcium wave initiated within an astrocyte causes vasoconstriction or vasodilation. -calcium vasoconstrict or vasodilate -astrocytes= can release different compunds, some vasodialtion and some vasoconstriction= not clear what this system exactly is

Question 19

How is vascular tone linked with neuronal activity?

Answer 19

-Neuronal activity causes dilation of blood vessels. -if you stimulate neurons in the brain= have to have change in blood flow in the brain -tight regulation between neural activity and blood flow, this is mediated by astrocytes

Question 20

How can astrocytes sense metabolic needs of neurons?

Answer 20

• the blood vessels need to be told when neurons are active and when they need nutrition
• astrocyte pick up when cells are firing and communicate with blood vessels
• do it via this calcium wave system , create vasodilation or vasoconstriction

Question 21

What happens to glia in disease?

Answer 21

-Diseases are associated with loss of any glial function: - Loss of uptake of NT: Causes excessive stimulation of neurons and ultimately death. -Treatment of epilepsy: GABA uptake inhibitors - Loss of Potassium uptake: Changes in water balance (cerebral oedema?) -glial cells change in disease -connected to different types of neurodegeneration -if you lose the ability to uptake NT this causes excessive stimulation (depolarisation) which will lead to tehir deatha s they don’t have the energy to maintain that= this is what happens in strokes -epilepsy= -cerebral oedema= in injuries, brain tumours, swelling of the brain

Question 22

What is gliosis?

Answer 22

-Gliosis: -Hypertrophy and hyperplasia of glial cells. -Occurs in virtually all diseases of CNS.: Increase expression of intermediate filaments (e.g. glial fibrillary acidic protein) -change in glial cell that makes it bigger and causes it to be more of tehm, proliferation -gliosis= the term referring to changes in glia in disease

Question 23

What are the functional changes brought about by gliosis?

Answer 23

-Altered potassium channel expression -NT uptake affected -Energy metabolism affected - Water balance affected. -gliosis is a protective response, try to isolate the injured area and spare the rest of the brain= but in the injured area= there are differences in the glial cells that detrimentally impact the neurons -gliosis results in functional changes in the affected area but protects the rest of the brain

Question 24

What is the altered water balance in gliosis?

Answer 24

• Decreased potassium channel expression and/or Aquaporin expression - Linked with problems in maintaining water balance=> oedema -in many disease, = swelling -change in potassium means change in water (osmosis)

Question 25

What is De-differentiation, does it mean that the CNS can rebuild itself?

Answer 25

A small number of gliotic glia proliferate. -Some express early stem cell markers (e.g., Pax6, Hes5) -glial cells can proliferate -can express early stem markers -the red marker= marker of proliferation -the glial cells divide -maybe can regenerate? in humans get proliferation but not the healing -they de-differentiate, go back to early stem cell and can change the cell type

Question 26

Summary?

Answer 26

• Glial are not just “brain-filler”
• Functions:
  1. Deactivation of NTs-eg glutamate and GABA
  2. Soak up potassium
  3. Provide energy metabolites to neurons.
• Glial Communication:- Short range: gap junctions - Long range: calcium waves
• Important for modulating neuronal activity
• Important for modulating blood flow.
• Role in CNS disease