Regeneration In CNS & PNS Flashcards
Current treatments for spinal cord injury
Spinal decompression
Neuro protection (steroid treatments, hypothermia - rare cases)
Rehabilitation (only certified treatment)
Assistive devices
Spinal decompression
After trauma, damage to spinal cord causes swelling
Surgical decompression of cord reduces the enlargement
Peripheral nerve regeneration
Stumps of growing axons
Central nerve regeneration
Do not regenerate - Die
Successful CNS regeneration - lamprey
Can fully regenerate its spinal cord after transection
Within 3 months- able to swim, burrow and flip around like normal
Repair and regeneration occurs after re transection
PNS vs CNS regeneration
Axon regeneration fails in CNS because of inhibitory environment and lack of regenerative ability of CNS axons
PNS axons regenerate because highly regenerative ability and permissive environment
PNS regeneration: cut vs crush
Cut: not as good as crush - larger task to accomplish
Crush: lesions regenerate better due to intact ECM. Acts as guidance channel for regrowth
Wallerian degeneration in PNS: conditions for successful regrowth
Schwann cells must be present and form bands of bungner
Lesion gap must also be vascularised and fibroblasts must for connective tissues
Grafts of extracellular matrix tubes into a cut nerve are insufficient to promote regeneration
Schwann cells needed
Recovery after PNS injury (crush) regeneration rate
Regeneration rates vary but usually around 1-1.5 mm/day in successful cases
PNS regeneration: importance of schwann cells and timing
Schwann cells in dense gated peripheral nerve only remain permissive for 2-3 months
Problem? Human rate of repair is very slow
Results? Proximal structures well innervated, distal structures poorly Innervate
Muscle end plates lose ability to become reinnervated after ~1yr
Muscles can become severely atrophied in absence of innervation
Using PNS environment within the CNS for repair
CNS injury
PNS nerve graft transplanted to create bridge for regrowing axons
Results - axons grew into the graft but not beyond (back into CNS)
Precondition lesions of the peripheral inside a robust regenerative response in CNS
Crushing the peripheral nerve enhances CNS regeneration within spinal cord of dorsal column axons
Upregulated series of genes (GAP 43)
High level of regeneration in sensory neurones
Have to do peripheral injury before CNS injury so not clinically relevant
Shown to work in optic nerve too but not motor axons
Intrinsic mechanisms to allow repair
Neuron cell survival
Axon elongation
Axon guidance to target
Appropriate target interaction and synapse formation
Activation of target in functionally meaningful way (functional repair)
Vascular supply
Regeneration (long distance?), replacement
Neuronal plasticity - nearby neurons take over the function of damaged neurons
Neuronal plasticity: developing nervous system
High potential for plasticity
Neuronal plasticity: adult
Low plasticity and low regenerative abilities
Is plasticity a more viable option for repair?
Axonal degeneration
Regeneration (we want this but not really happening)
Plasticity (can it take over? Usually more effective )
Development of the nervous system and the critical period
Critical period in nervous system: time during which reduction of neuronal numbers, remodelling of synapses and strengthening of connections occurs
Most influential time - permanent connections
Brain more plastic
Plasticity and critical period - visual system
Left and right eyes take info back to visual cortex
<5 yrs old - one eye covered, other eyes visual field expanded by plasticity
Adult - no change
How and why does the critical period close?
Perineuronal nets (PNNs)
Formed at the end of critical period
Composed of ECM including CSPGs which covers cell soma and proximal d writes of certain classes of neurones
PNNs inhibit plasticity in adult CNS
Partial PNN knockout in mice display increased plasticity following adult CNS damage
Successful steps in growth cone formation in sea snail
damage to axon membrane, entrance of calcium into axon and cell body, increase membrane depolarisation, more calcium due to calcium channels, activates calpanes, digests cortex of axon, spectrin, actin and MTs become depolymerised, vacuole internalisation, membrane begins to collapse at cut end, reseals, ca2+ return to normal, actin and MTs repolymerised, actin filaments assemble to generate force at leading edge of lamellipodium, MYS polymerise and point +ve ends towards plasma membrane, extending cell
Neurite outgrowth and axon growth cones formation
Axotomy allows calicium into axon
In absence of calcium, regeneration fails and static endbulb formed
Growth cone formation
Recycling of axonal molecules (actin,tubulin)
Transport vesicles in their way to axon terminals
Local translation of mRNAs
Take in from environment
Axotomy leads to upreg of new proteins in cell bodies. Growth cone regen may happen too fast for these molecules to arrive
Regeneration & repair - CNS myelin inhibitors
Nogo-A, MAG, OMgp are expressed on oligodendrocytes - inhibit axon regeneration
Affect signalling, block pathways if not functioning properly
Future treatments: combatting myelin debris?
Goldfish neurones successfully grow over goldfish oligodendrocytes
3T3 cells
CNS myelin - no processes
PNS myelin - small amount
SCH neurones
CNS myelin - no regrowth in mammals
Lamanin
CNS myelin from rat - avoid CNS myelin so shows inhibition of mammalian meyelin
