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Developmental Neurobiology > Lecture 23- Axon Regeneration > Flashcards

Lecture 23- Axon Regeneration Flashcards

1
Q

Can neuron survive an axon injury?

A

-A neuron may survive axotomy (at least for a time) -axotomy= severed -the proximal part can survive, but it depends -only in the PNS in mammals

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2
Q

Can mammals regenerate axons in the CNS?

A

-Mammalian CNS injury: no axon regeneration

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3
Q

What happens when you have an injury in the CNS?

A
  • Distal portion of severed axon degenerates
  • Dystrophic neurons no growth cone, no crossing of lesion site
  • Some compensatory axon sprouting
  • only short distance
  • the axon that is spared tries to compensate by more sprouting but this will only somewhat help functionality
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4
Q

What is the aim in axon regenaration?

A

1: Survival of neuron
2: Generation of growth cone= through lesion site
3: Growth of axon=through lesion site
4: Extension of axon= beyond lesion site
5: Re-establishment of connection with target
6: Functional recovery
- most of the research is concentrating on the first 4 stages

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5
Q

Where can spontaneous axon regeneration occur?

A

-Peripheral nervous system Neuron can have axon in both CNS and PNS, but only regenerates in PNS - CNS of invertebrates and lower vertebrates (dorsal root ganglion= have process both in pNS and CNS but only PNS can regenerate)

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6
Q

What is often used as a model for axon injury?

A

-SCI and optic nerve crush are models of axon injury

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7
Q

How was it shown that peripheral nerve grafts can support CNS axon regeneration?

A
  • damage a nerve and then provide a peripheral graft, the axon regenerate in the PNS nerve graft but not in the CNS
  • CNS axons are capable of regeneration when
  • Regrowth stops at CNS -Same result seen in injured spinal cord
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8
Q

How do the mature CNS and PNS environments differ?

A
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9
Q

What happens to a neurite in vitro when it comes into contact with oligodendrocytes?

A

-In vitro: contact with oligodendrocytes and CNS myelin extracts prevents neurite outgrowth

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10
Q

What is myelin?

A
  • Myelin is part of the specialised oligodendrocyte membrane - Composed of lipids and proteins
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11
Q

What is Nogo?

A

-a myelin associated inhibitor -one of the inhibitory factors in myelin -Nogo gene generates 3 isoforms: Nogo A, B and C -Nogo A also has inhibitory domains in its N-terminal sequence -Nogo66 is the inhibitory domain that is common to all nogo isoforms

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12
Q

What is the receptor for Nogo?

A

-Nogo receptor (NgR1) on neurons throughout CNS

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13
Q

Does NgR1 have an intracellular domain?

A

-NgR1 lacks intracellular domain

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14
Q

What are the signalling subunits of NgR1?

A
  • p75 / TROY and Lingo-1 act as signalling subunits -they activate Rho GTPase= causes collapse of growth cone (chnage in cytoskeleton) -Rho activation = growth cone collapse
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15
Q

What are the inhibitory componenets of myelin?

A
  • Nogo-A, MAG and OMgp have different structures but bind same receptor complex
  • MAG and OMgp inhibit neurite outgrowth in vitro
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16
Q

What happens in Nogo knockout mice?

A
  • Results from Nogo knockout mice vary in different studies
  • Treatment with antibody that blocks Nogo-A induces axon sprouting / regeneration
17
Q

What prevents axon regeneration?

A

-Extrinsic factors: the lesion evironment: Inhibitory components in myelin debris -Nogo, MAG, OMgp are components of myelin which inhibit axon regrowth -Inhibitory myelin components signal via receptors (NgR1, NgR2) and co- receptors (p75 / TROY, Lingo-1) on the neuronal membrane - Contact with myelin inhibitors induces cytoskeletal changes in the neuron:leads to growth cone collapse, prevents axon growth through lesion site

18
Q

What is the astrocyte response in injury in the CNS?

A
  • astrocytes perform a variety of roles= important in support roles
  • after disease or trauma to the CNS= respond and get astrogliosis = the astrocytes change, become bigger, and thicker
19
Q

What is the glial scar?

A

-glial scar= major component are the big astrocytes, but a avriet yof cells in the glial scar -physical barrier= astrocyte shave dense processes so the axons cannot penetrate -also chemical -Forms over time following injury -Physical and chemical barrier to axon regeneration

20
Q

What is elevated in the glial scar?

A
21
Q

What does the glial scar do?

A

-The glial scar limits the spread of immune cells -limits the inflammation to a localized area, thus it is good - The inflammatory response is necessary but inefficient - debris / other debris - Immune cells release both growth-promoting and neurotoxic substances - may increase area of damage -the immune cells can stick around for a long time, even years= chronic neuroinflammation= probably unhelpful

22
Q

Is the inflammatory response started by the astrocytes necessary and efficient?

A
  • The inflammatory response is necessary but inefficient
  • debris / other debris
  • Immune cells release both growth-promoting and neurotoxic substances
  • may increase area of damage
  • when the glial scar is removed= the immune cells are released and damage more area
23
Q

What is the effect of guidance molecules in injury?

A

-Developmental axon guidance molecules are expressed in the injured CNS -Still present in mature CNS or re-upregulated following injury -Many repulsive guidance molecules - Expression on neurons, astrocytes, oligodendrocytes/myelin

24
Q

What happens at at a lesion site in the CNS?

A

-Multiple Eph / ephrin interactions at the lesion site -e.g. Interaction of EphA4 (neuron) with ephrin B3 (myelin) Interaction of EphA4 (astrocytes) with ephrins (on reactive astrocytesn as well) -some developmental guidance molecules are still expressed in the injured adult CNS -mostly repulsive guidance cues -have ephrin and semaphorin -eph receptors= tyrosine kinase receptors

25
Q

What happens in EphA4 knockout mice?

A

-EphA4 knockout mice have increased axon regeneration and functional recovery following SCI (spinal cord injury)

26
Q

What prevents axon regeneration (the long one)?

A

-Extrinsic factors: the lesion evironment 1.The glial scar & inflammation - glial scar is a chemical and physical barrier to axon regeneration - e.g. upregulation of CPSGs inhibitory ECM component - inflammatory response is inefficient and contributes to toxicity 2.Axon guidance molecules - repulsive axon guidance ligands and receptors are present / upregulated after injury (ephrin, semaphorin, slit, netrin families) - in glial scar, oligodendrocytes/myelin, neurons - causes growth cone collapse and prevents axon regrowth into lesion site

27
Q

What are the differences between regeneration and development environment?

A

1.Regeneration: -environment : Oligos and myelin Reactive astrocytes Inflammatory -guidance signals: Re-upregulated but inhibitory -growth signals: Not expressed in way that supports regrowth 2. Development: -non-myelinated, no astrocyte reactivity, non-inflammatory -guidance signals: re upregulated, but inhibitory -growth signals: abundant -comparison of the dev. plus adult environment = normally would only grow in development with regeneartion must deal with :

28
Q

What is also true of the regeneration vs development?

A

-must grow much longer way than in development as the adult is larger than the baby, -Mature CNS axons are capable of regeneration -How well can mature CNS neurons actually regrow?

29
Q

What are the intrinsic neuronal differences between the regeneration vs development?

A

-Developing and mature neurons respond differently to their environment inhibitory myelin components -Even in an optimal (non-inhibitory) environment, mature CNS -We need (lots of) regenerating axons to travel a long distance

30
Q

What do younger neurons have higher than the older neurons?

A

-Young neurons have higher levels of cAMP, how to boost the intrinsic ability of neurons to grow, the developing neurons= have - Acute effect: conversion of repulsive into attractive signal - Long term effect: activation of transcription factors

31
Q

What does cAMP do?

A

-cAMP promotes neurite outgrowth -cAMP and Nogo and MAG and OMGp go against each other

32
Q

Can the regeneration be helped with higher cAMP?

A

-yes -one way of improving the regeneration = prevent cAMP breakdown or put in cAMP homologue

33
Q

What is the mTOR/PTEN and protein synthesis?

A
  • regenerating axons need increased protein synthesis
  • mTOR levels decrease in neurons with age, and following axotomy Phosphatase and tensin homolog (PTEN) is a negative regulator of cell growth PTEN deletion = increased protein synthesis
  • if you manipulate PTEN= negative regulator of mTOR/PTEN
34
Q

What happens to mice with PTEN deletion?

A

-PTEN deletion increases axon regeneration and sprouting following injury -PTEN deletion enhances growth cone protein synthesis -Allows extensive regeneration though inhibitory lesion site -surprisingly good at increasing sprouting and regeneration

35
Q

What are the intrinsic factors preventing axonal regeneration?

A

-Intrinsic factors: capacity of the neurons to regrow - mature CNS neurons have not lost the capacity to regenerate axons, but their intrinsic capacity for growth has diminished with age - mature neurons have lower levels of cyclic AMP (cAMP) than developing neurons, which alters the growth cone response increasing cAMP in mature neurons a potential treatment strategy - regenerating axons must travel longer distances than developing axons mice with PTEN deletion have enhanced protein synthesis, promoting axon growth through the inhibitory lesion environment

36
Q

Is the capacity of neurons diminished over time?

A

-cell intrinsic mechanisms: capacity of the neurons to regrow -diminished in mature compared to developing neurons

37
Q

What is the evolutionary explanation for the reduced regenerative ability of mature neurons?

A

-The types of injury that would damage the CNS would almost certainly lead to rapid demise in the wild before regeneration could take place -The most likely evolutionary explanation for the loss of CNS regenerative capacity is that this is an unselected by-product of gaining the increasingly complex nervous systems that selection pressures have favoured over time

38
Q

What treatments are developed to promote axon regeneration?

A
  • Multiple interventions? - Neuroprotective factors - Block inhibitory factors in myelin - Block repulsive axon guidance molecules -Digest CSPGs in glial scar - Inhibition of inflammatory response - Promote re-myelination of surviving neurons - Neurotrophins to promote regeneration - Transplantation of cells - Olfactory ensheathing cells: neuroprotective - Human embryonic stem cells: re-myelination of spared axons - Induced pluripotent stem cells

Developmental Neurobiology (32 decks)

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