Astrocytes and Neurons

Question 1

Compare PNS and CNS neurons

Answer 1

PNS
- Cell bodies outside the brain or spinal cord

CNS
-Central neurons have cell bodies within the brain and spinal cord

Question 2

Compare white and grey matter

Answer 2

• White matter is axons (myelinated = white)

- Grey matter is the cell bodies

Question 3

What is a neuron?

Answer 3

• Basic structural and functional unit of the nervous system
• Information processing unit
• Responsible for generation and conduction of electrical signals
• Communicate with one another via chemicals released at the synapse
• Heterogeneity
• Supported by neuroglia comprising of several different cell types

Question 4

Describe anatomical features of the neuron cell body

Answer 4

• Large nucleus
• Prominent
  nucleolus
• Abundant rough ER
• Well developed Golgi
• Abundant mitochondria
• Highly organised
  cytoskeleton
• HIGHLY ORGANISED
  METABOLICALLY
  ACTIVE CELL

Question 5

List types of neurons

Answer 5

• Unipolar (one process)
• Pseudounipolar (one process which serves as both an axon and a dendrite)
• Bipolar (one axon and one dendrite)
• Multipolar (1 axon and 2 or more dendrites)
• Anaxonic (no axon)

Question 6

List locations of multipolar neurons

Answer 6

• Motor
• Pyramidal (hippocampus)
• Purkinje cell (cerebellum)

Question 7

List locations of bipolar neurons

Answer 7

• Retinal neuron

- Olfactory neurons

Question 8

List locations of unipolar neurons

Answer 8

• Touch and pain sensory neuron

Question 9

List locations of anaxonic neurons

Answer 9

• Amacrine cell

Question 10

Describe classification of neurons based on function

Answer 10

• Sensory (transmit info about the surrounding environment to CNS neurons)
• Motor (innervate muscle and stimulate contraction)
• Interneurons (comunicate between 2 neurons)

Question 11

Describe organisation of neuronal circuits

Answer 11

• Divergence (spreading stimulation to multiple neurons or neuronal pools in the CNS, one neuron communicates with multiple others)
• Convergence (provides input to a single neuron from multiple sources - eg eye)
• Serial (Neurons work in a sequential manner)
• Parallel processing (individual neurons or neuronal pools process information simultaneously)
• Reverberation (feedback mechanism which may be excitatory or inhibitory)

Question 12

Describe the process of action potential in neurons

Answer 12

• Incoming signals received at dendrites, outgoing along the axon
• Action potential is a brief reversal of electrical polarity across a cell membrane
• In a resting neuron, the resting potential is -70mV (more negative on inside, gradient of sodium and pottassium with more sodium out and more potassium in, maintained by sodium potassium pump)
• Excitatory signals at dendrites opens ligand gated sodium channels and allows sodium in, causing depolarisation. This creates a current which moves to the axon hillock.
• There are voltage gated channels on the axon hillock, which open and close depending on voltage
• Action potential then travels down the axon
• For an action potential to occur, the threshold is -55mV which opens voltage gated channels. Sodium channels open more quickly causing influx, increasing voltage in positive feedback until peak is +40
• Falling phase is where sodium channels close, and potassium channel opens allowing potassium to move out and repolarisation occurs in the falling phase
• There is a negative overshoot called hyperpolarisation. VIa sodium potassium pump, the resting potential returns.
• Absolute refractory period is from start of action potential to resting membrane value (sodium channels open and then inactivated when closing)
• Relative refractory period during hyperpolarisation, where a stronger signal is needed for a response
• At the axon, during an axon potential sodium influx depolarises the adjacent channels causing the action potential to propagate. The refractory period ensures the action potential travels one way.
• Concentration of voltage gated channels are higher in the axon than in the cell body

Question 13

Describe neurotransmitter release and synaptic function

Answer 13

• Action potential opens voltage gated calcium channels at the synaptic terminal
• Calcium influx at the synaptic terminal
• This activates release of neurotransmitter into the synaptic cleft
• Neurotransmitters then bind to the target receptors causing sodium channels to open

Question 14

Glia as architects of CNS formation and function (Nicola J Allen) 2018

Answer 14

• Microglia are resident immune cells of the brain - enter from the periphery in early development. Regulate synaptic pruning, clear apoptotic neurons and interact with multiple CNS cell types
• Dynamic bidirectional interactions of neurons and glia (glia regulate neuron number and neurons regulate glial cell function)
• Glia are involved in neuronal migration - radial glia support radial migration of neurons. Polarised mRNA transport and localized protein translation suggests regulation of neuronal development.
• GLial cells coordinate timing of neuron differentiation
• Astrocytes regulate neurotransmitter uptake - eg. by glutamate transporters
• Regulation of ion homeosasis - clearing potassium from ECS
• Astrocytes make glycogen -> lactate
• Oligodendocytes myelinate axons, and change the conduction velocity

Question 15

Astrocyte crosstalk in CNS inflammation (2020)

Answer 15

• Astrocytes arise from neural progenitor cells in the subventricular zone and migrate alone radial glia processes to populate the brain
• Contribute to formation of the blood brain barrier
• Astrocytes important in MS, AD, PD, HD, ALS
• Blockade of astrocyte signalling via NF-kB in optic neuritis, experimental autoimmune encephalomyelitis and spinal cord injury improves clinical outcomes. NFkB stimulated by pro-inflammatory stimuli
• Lactosylceramide is also upregulated in EAE.
• Aryl hydrocarbon receptor limits NFkB signalling, made by commensal bacteria in the gut
• Microglia-astrocytes have crosstalk in diseases and use cytokines to modulate CNS inflammation
• When activated, astrocytes release NO or glutamate or downregulate neurotransmitters leading to neuronal death.
• Also impact leukocytes
• Oligodendrocytes play an active role in CNS immunomodulation (responsivve to inflammatory stimuli form astrocites). Also affect the BBB
• Astrocyte foot proceses form the glia intimans which constitutes the BBB. In neuroinflammation, there is leakiness and infiltration of peripheral immune cells. VEGF is important in this. Astrocutes promote stability by sonic hedgehog.
• Astrocytes are important in recruitment of leukocytes
• Microglia have an immune memory
• Histone methylation and acetylation linked to astrocyte control. Methylation inhibits gene expression

Question 16

Reactive astrocytes: production, function, therapeutic potential

Answer 16

• GFAP upregulated by reactive astrocytes - has in the past been used to monitor reactivity
• Microglia have two polar states, M1 are inflammatory mediator upregulators, and M2 immunosuppressive (destructive to synapses)
• Astrocytes have A1 inflammatory and A2 ischaemic states (promote survivial, growth, synapse repair)
• Microglia induce A1s by releasing IL1a, TNFa, and complement component subunit 1q. Decreased ability for inducing synapse function, loss of phagocytic ability, and loss of ability to promote growth. Complement C3 is upregulated in A1. A1 are present in many models of moise disease.
• A1 formation could be prevented by delivery of neutralising antibodies to TNFa and ILa, NFkB or Stat3 could also be targetted.
• NFkB pathway activated by inflammatory agens
• A2 upregulates cell proliferation via JAK STAT3 (scar formation and recovery)
• Microglia may be activated by neuron damage, which then would activate astrocyres to become A1
• A1 may be present to clear bacteria

Question 17

Describe function of dendrites and how it performs its function

Answer 17

• Receive input
• MAP2B microtubule stabilising protein
• Neurotransmitter receptors
• Increase SA of the neuron, often covered in spines which receives signals (vary in number with electrical activity)

Question 18

List types of dendrites

Answer 18

• Primary dendrites arise from cell body

- Secondary from primary dendrites

Question 19

Describe different spine morphologies

Answer 19

• Stubby
• Thin
• Mushroom
• Filopodium

Question 20

Describe function of axons

Answer 20

• Output - transmit signal
• Emerge from axon hillock, usually one per cell but may branch after leaving cell body (axon collaterals)
• Do not have spines
• Abundant intermediate filaments and microtubules
• Contain many mitochondria
• Cable properties for constant conduction speed

Question 21

List types of synaptic terminals

Answer 21

• Bouton

- Varicosities

Question 22

Describe organisation of synapses

Answer 22

• Most synapses are axo-dendritic, which are usually excitatory (glutamate, acetylcholine)
• Axo-somatic (cell body) and axo-axonic synapses usually inhibitory or modulatory (GABA, dopamine)
• Competing inputs are integrated in the postsynaptic neuron
  (neuronal integration)

Question 23

Describe structure of astrocytes

Answer 23

• 40% cells in human brain
• Many thin processes
  around capillaries (left),
  synapses, surface of
  neurons.
• Cytoskeleton - GFAP (Glial
  fibrillary acidic
  protein),microtubules, actin.
• Expression of vimentin
• glycogen granules
• Rough ER, Golgi apparatus
• Large nucleus.
• Light cytoplasm
• Connect to blood vessels, neurons, nodes of Ranvier, microglia, oligodendrocyte precursor cells

Question 24

List types of astrocyte

Answer 24

• FIbrous (located in the white matter)
• Protoplasmic (located in the grey matter)
• Velate (cerebellum)
• Type B cell (subventricular zone)

Question 25

List functions of astrocytes

Answer 25

• Modulation of synaptic function: synaptogenesis and
  synaptic pruning
• Metabolic function: production of cholesterol and lactate
• Maintenance of the BBB
• Regulation of blood flow
• Neuroprotective: release of growth factors, transport proteins for nutrients and metabolites + neuronal trophic factors
• Recycling of neurotransmitters, potassium reservoir
• Production of anti-inflammatory cytokines
• Astrocyte ablation worsens amyloid pathology (mouse study)

Question 26

Describe astrocyte dysfunction in neurodegeneraiton

Answer 26

• Increased glutamate cytotoxicity
• Increased levels of Calcium and ATP release
• Increased production of nitric oxide
• Accumulation of superoxide dismutase
• Formation of glial scar

Question 27

Describe blood brain barrier

Answer 27

• The blood-brain barrier is formed by the very tight
  association of brain capillary endothelial cells.
• It is essential for controlling entry of molecules and ions from the general circulation into the central nervous system.
• Astrocytic endfeet enwrap endothelial cells, providing the gateway for nutrients etc into the CNS, and removal of
  metabolites from the CNS
• AQP4 in the brain is involved in clearance of amyloid in the brain during sleep (also potassium buffering, neuroinflammation, cell mutation.etc)

Question 28

Describe radial glia and their function

Answer 28

- Span the cortex radially
from the inner to outer
layers.
- Are important for neuronal
migration.
- Examples are the
Bergmann glia in the
cerebellum and the Muller
cells in the retina.
- Can give rise to neurons, astrocytes and ependymal cells

Question 29

List astrocyte targeted therapeutic approaches

Answer 29

• Virtual gene delivery (neurotrophic and growth factors)
• AQP4 restoration
• Cell replacement (neurogenesis, NSC transplantation)
• Drug treatments (I2IR ligands, GLT1 promotors)