Lecture 21/22 Neurotransmission and Inflammation

Question 1

What are 4 important roles of astrocytes beyond structural support, buffering ions and removal of transmitter

Answer 1

1. Release of neurotransmitters: Gliotransmission& glioneural functional units. (eg. astrocytic adenosine induces sleep via caffeine receptors)
2. Regulate synaptic transmission, Expressing receptors
3. Produce and release neurotrophins, precursor for neurons?
4. Form scaring following damage (impeding axonal growth), immune activation of T cells

Question 2

What are the 4 different types of astrocytes in human cortex

Answer 2

Protoplasmic,
Interlaminar astrocytes,
Fibrous astrocytes,
Polarised astrocytes

Question 3

Compare the Protoplasmic v Fibrous astrocytes, structure and function

(- GFAP: glial fibrillary acidic protein)

Answer 3

P: most common type, residing in layer 2 and 6.
F: found in white and gray matter
P: GFAP pos. processes do not overlap: domain organisation,
Role is to coordinate between cells in its domain: eg regulate blood flow in response to increased synaptic transmission, helps to integrate activity between 10 nerve cells, 5 blood vessels and many synapses.
F: GFAP pos. processes intermingle.
Role is to support neurons and respond to brain injury through forming scar tissue.

Question 4

What are microglia and their role

Answer 4

They are surveyors of the brains microenvironment.

1. resident macrophages of debris, plaques, bacteria etc
2. Mediate the brain immune response
3. Modulate neurotransmission, synaptic transmission through interactions with astrocytes (releasing ATP-> astrocyte glutamate-> AMP synapse-> increase activity)
4. Help sculpt the brain during development by phagocytosing “extra” neurons

Question 5

What is the Pericytes role and link to Alzheimers disease + stroke

Answer 5

Pericytes encase endothelial cells in the brain capillaries, instructing them to maintain the BBB and stabilise them.
In Alzheimers+ stroke, it is thought that BBB is compromised due to losing pericytes allowing big toxic blood proteins and destructive immune cells in the brain

Question 6

Describe the path of neuron transmission via chemical messengers (although some neurons use electrical)

Answer 6

1. Depolarisation of the presynaptic neuron leads to increase in Ca2+ leading to release of neurotransmitter from the presynaptic terminal
2. NT diffuses across the synaptic cleft and acts/binds on neurotransmitter receptors on the post synaptic target neuron.
3. There is effect: eg. ion channel opening or generation of 2ndary messenger leading to either excitation or inhibition.
4. Termination of NT action is by metabolism and or re uptake into the neurons or glial cells (astrocytes) by specific transporter proteins

Question 7

What is chemical neuroanatomy and why is it important

Answer 7

It is the study of anatomical localisation of NT systems important bc brain is complex and the action of a drug will not only depend on NT system but also anatomical localisation

Question 8

Compare the speed of action of Neurotransmitters, neuromodulators and neurotrophic factors and give example of each- who produces them

Answer 8

NT: Have both fast and slow depending on the receptor subtype acting on

• Fast acting work via ion channels (eg. glycine, GABA, glutamate
• Slow acting via GPCRs (eg. dopamine, neuropeptides, GABA, Ach)

Neuromodulators: Produce slower pre and post synaptic responses. Released by nerve cells and astrocytes (eg. adenosine)

Neurotrophic factors: Work over long time scales. Released by non-neuronal cells (astrocytes, microglia). Act on Tyrosine kinase type receptors to mediate growth, morphology, functional properties, survival promoting effects in the NS. (eg. Nerve growth factor, BDNF)

Question 9

What is the innate immune response vs adaptive including usual cells involve

Answer 9

II: 1st line of defence mediated by macrophages. This is nonspecific and includes the complement cascade to help cells remove pathogens.
AI: specific response mediated by T cells and B cells

Question 10

How do Astrocytes help the immune response in brain

Answer 10

Can release pro-inflammatory and anti-inflammatory molecules. 
Can present antigens to activate the adaptive immune system- draw T cells into the brain
Can phagocytose (poorly)

Question 11

How do Microglia help to mediate the immune response in brain - good or bad)

Answer 11

• Phagocytose apoptopic debris, toxic chemicals (amyloid plaque), bacteria.
  However during inflammation, can phagocytose healthy neurons, make brain disease worse.
• Can present antigen to activate the adaptive immune response- draw T cells in the brain

Question 12

What are activators of Neuroinflammation and give example of related disease

Answer 12

• Toxic proteins: Amyloid (AD), tau, synuclein (PKd), prions, mutant SOD.
• Infectious agents- HIV- (aids dementia)
• Myelin (MS)
• Systemic inflammation and infections (Interferon gamma, ILbeta

Question 13

What are the cell signalling molecules involved in Neuroinflammation and give example

Answer 13

• Cytokines- cell signalling molecules (proinflam: TGF alpha)
• Chemokines- draw immune cells into affected regions
• Labile messengers - prostaglandins
• Adhesion molecules (ICAM - neutrophils, VCAM - t cells).

Question 14

Which came first? Acute insult (stroke) or chronic disease (amyloid protein in AD) and what is the progression of steps one way

Answer 14

Inflammatory markers change early in disease so perhaps more causal

1. Neuroinflammation
2. Microglial activation
3. inflammatory molecule production
4. Neuronal cell death

Question 15

What is the main disorder relating to neuroinflammation

Answer 15

MS- multiple sclerosis: autoimmune disease against myelin sheath

Question 16

What are other places where Neuroinflammation takes place apart from cortex

Answer 16

• Meningeal inflammation: infection- meningitis
• Choroid plexus
• Capillaries - endothelial cells, pericytes.