Neuronal Nogo and Motor Neuron Disease

Neural Injury and RepairNoam Y. Harel, MD, PhD12 November 2013Brain and Behavior1DisclosuresI do not have any financial or other conflicts of interest to disclose for this learning session.

I do not affirm that all discussions of drug use will be consistent with either FDA or compendia-approved indications. Off-label and experimental drugs may be discussed.

Learning ObjectivesRecognize differences between axonal injury and repair in the PNS versus CNS.Understand levels of neural plasticity from subcellular to network plasticity.Recognize approaches and targets for improving neural repair.Understand principles of neurorehabilitation essential in conjunction with any other drug, cellular, or engineering-based treatments.

Injury: soma or nerve?

Scenery: PNS or CNS?

Machinery: intrinsic, extrinsic

Strategery: Targets for repair and recovery

Injury: SomaExcitotoxicity (may be acute or chronic)

Ischemia, trauma, etcDecreased ATPInc intracellular Na+, Ca++Membrane DepolarizationIncreased action potentialsGlutamate releaseDecreased glutamate reuptakeIncreased extracellular glutamateCell deathSPREADING EXCITOTOXICITYDoble 1999NECROSIS INFLAMMATIONAPOPTOSIS NO INFLAMMATIONInjury: Soma

DP AgamanolisChromatolysisInjury: NerveRay Jurewicz

Deumens et al.

Focal demyelinationAxon disruptedEndo. disruptedPeri. disruptedEpi. disruptedPrognosis

Good (weeks)

Fair (mos)

Poor(surgery mayhelp)....NERVE CONDUCTION STUDIES/ELECTROMYOGRAPHY:Demyelination: Decreased conduction velocityAxonal loss: Decreased action potential amplitudeIntra-axonal organelle and microtubule breakdown (minutes-hours)

Schwann cells begin axon breakdown and recruit more cells (hrs-days)

Macrophages enter, accelerate process (1-2 weeks)

Path cleared for axons to regrow proximal-->distal (weeks-months)

Injury: NerveWallerian Degeneration

Scenery: Peripheral vs CentralPNSCNSRamon y CajalScenery: Peripheral vs Central

WallerianDegenerationWallerianDegenerationPNS yesCNS failScenery: Peripheral vs Central

PNS yesCNS failSchwannshelpOligodendrocytedebris,astrocytes,scarringhurtMachinery: Intrinsic vs Extrinsic

Akbik et al., 2012CNS EXTRINSIC InhibitorsCNS Cell TypeInhibitory ProductOligo-dendrocytesMyelin-associated inhibitorsAstrocytesChrondoitin sulfatesAstrocytes+FibroblastsGlial/fibrous scar tissueScenery: Peripheral vs Central

Intrinsicgrowthpotential(1-3 mm/d)Sluggishgrowthpotential(0.1 mm/d)PNS yesCNS failMachinery: Intrinsic vs ExtrinsicSeo & Kiyama, 2011PNS INTRINSIC AdvantagesRegeneration-Associated GenesPNS neurons possess receptors and signal transduction machinery allowingthem to grow in response to neurotrophins, retrograde injury signals

cAMPA number of RAGs have been shown to be important for neurite outgrowth and/or regeneration. These include c-Jun (Raivich et al.2004), activating transcription factor-3 (ATF-3) (Seijffers et al.2006), SRY-box containing gene 11 (Sox11) (Jankowski et al.2009), small proline-repeat protein 1A (SPRR1A) (Bonilla et al.2002), growth-associated protein-43 (GAP-43) and CAP-23 (Bomze et al.2001).

Machinery: Intrinsic vs ExtrinsicLetourneauWhat does regeneration look like?

Growth ConesMachinery: Intrinsic vs ExtrinsicWhat does regeneration look like?

Ramesh 2004Dickson 2002Growth ConesDynamic growth through regulation ofactin and microtubule polymerization/depolymerization

Hammarlund et al., 2009Machinery: Intrinsic vs ExtrinsicWhat does FAILED regeneration look like?Ramon y Cajal

Retraction Bulbs (of Cajal)besides CNS vs PNS, what else reduces the intrinsic growth potential? AGESynapse regulationReceptor regulationTransmitter regulationNetwork adaptationSproutingCNS PLASTICITY: A more realistic term than CNS regenerationShort-term, Long-termLong-termSynapses, receptors, transmitters

Lesch, Waider 2012Xu et al., 2009

Dendritic spinesAxonal boutonDendritic spineGlial cellNetwork adaptation

Sprouting: Use What You GotUninjuredDirect regeneration1235476RetargetingItinerant regenerationDirect proximal sproutingSprouting from neighborSprouting to neighborIndirect reroutingFIG 2 - Modes of circuit regeneration. Two schematic descending pathways are shown one synapsing on motor neurons controlling fine voluntary movements, and one synapsing on motor neurons responsible for postural control. Note that one of the fine voluntary motor neurons is not directly influenced by the descending pathway. After a partial lesion that injures the descending fine movement pathway, the motor neuron controlled by that pathway loses voluntary function. Over time, and with the aid of regenerative strategies, several modes of recovery may occur: 1) Precise regeneration from the severed fiber to the original target; 2) regeneration of the severed fiber to the original target via a haphazard/ectopic pathway; 3) sprouting from unlesioned heterologous neighboring fibers onto the denervated target neuron; 4) formation of synaptic relay circuits may occur; 5) sprouting of the injured fiber proximal to the lesion toward neurons neighboring the denervated target neuron.

Complexity Redundancy

VJ WedeenRedundancy PlasticityRecovery through Rerouting,not RegenerationRecovery through Rerouting, not Regeneration

Strategery: Repair and RecoveryTargets anyone?*class to fill-in*Improve cleanup macrophages instead of oligos? Reduce inflamm & scarring steroids; chondroitinases; etcAdd guidance scaffold Schwanns; olfactory ensheathing glia; etcReplace growth factors but can CNS neurons respond? gradients?Trigger RAGs cAMP modulators (rolipram); direct gene therapyActivate growth cones calcium; microtubule stabilizers (eg taxol)Block extrinsic inhibitors Mabs; receptor decoys; RhoA inhibitorsExcite circuits transmitter agonists; K+ blockers; electrical stim; etc Replace neurons Stem cellsRemyelinate axons Stem cellsRehabilitate!!Strategery: Repair and RecoveryTargets anyone? ESSENTIAL IN CONJUNCTION WITH ALL THE ABOVEpoint out difficulty of trying single agents in what needs to be a multi-faceted treatmentANY kind of activity/nerve stimulation:exercise, electrical stim, magnetic stim, etcLeads to increases in:growth factors, especially BDNFneurogenesisglial cell supportangiogenesissynaptogenesis

Activity Plasticity

Wu et al., 2008Circuits need PruningShore, 1997

14 yo6 yobirthconsolidationregrowthinjuryPlasticity isnt just GrowthEducation > ExertionSpecificity > SweatyLearning (or re-learning) a variety of skilled, task-specific, repetitive tasks is more beneficial than general exercise alone.

Skilled: Better stimulates cortical networksTask-specific:Real-life skills more motivating; prune unneeded circuitsRepetitive:to maintain gains/consolidate circuits, need to overlearn

Education > ExertionSpecificity > SweatyLearning (or re-learning) a variety of skilled, task-specific, repetitive tasks is more beneficial than general exercise alone.Rigorous, CONTROLLED clinical rehabilitation studies are woefully lacking, sorely neededIn both animals and humans, repetitive training in a specific task leads to improved performance in that task, without benefit in other tasks

From the spinal cord injury field

Cats trained to stand can stand but not walk betterCats trained to walk can walk but not stand betterRats trained to swim can swim but not walk betterRats trained to reach can reach but not climb betterHumans trained on treadmill can walk better on treadmill but not over groundDe Leon et al, 1998; Smith et al, 2006; Dobkin et al, 2006; Garcia-Alias et al, 2009Practice Makes Pigeonholed?

Practice Makes Pigeonholed?either he always plays the same role, or he was born with a magnum fused to his manus. Can you see Jason Statham playing the lead in a chick flick? Can you see David Schwimmer or Hugh Grant playing the lead in Crank? The Dilemma: How to broaden the benefits of task-specific training?

Practice variety of tasks within same broad categoryeg writing in print vs cursive letters, etc - Winstein and Wolf 2009

Random practice order rather than ordered blocksLearning ObjectivesRecognize differences between axonal injury and repair in the PNS versus CNS.Understand levels of neural plasticity from subcellular to network plasticity.Recognize approaches and targets for improving neural repair.Understand principles of neurorehabilitation essential in conjunction with any other drug, cellular, or engineering-based treatments.

BAPTISTE, D. C. & FEHLINGS, M. G. (2006) Pharmacological approaches to repair the injured spinal cord. J Neurotrauma, 23, 318-34.BRADKE, F., FAWCETT, J. W. & SPIRA, M. E. (2012) Assembly of a new growth cone after axotomy: the precursor to axon regeneration. Nat Rev Neurosci, 13, 183-93.CAFFERTY, W. B., MCGEE, A. W. & STRITTMATTER, S. M. (2008) Axonal growth therapeutics: regeneration or sprouting or plasticity? Trends Neurosci, 31, 215-20.HAREL, N. Y. & STRITTMATTER, S. M. (2006) Can regenerating axons recapitulate developmental guidance during recovery from spinal cord injury? Nat Rev Neurosci, 7, 603-16.KERSCHENSTEINER, M., SCHWAB, M. E., LICHTMAN, J. W. & MISGELD, T. (2005) In vivo imaging of axonal degeneration and regeneration in the injured spinal cord. Nat Med, 11, 572-7.KRAKAUER, J. W. (2006) Motor learning: its relevance to stroke recovery and neurorehabilitation. Curr Opin Neurol 1:84-90.PASCUAL-LEONE, A., AMEDI, A., FREGNI, F. & MERABET, L. B. (2005) The plastic human brain cortex. Annu Rev Neurosci, 28, 377-401.RAMON Y CAJAL, S., DEFELIPE, J. & JONES, E. G. (1991) Cajal's degeneration and regeneration of the nervous system, New York, Oxford University Press.Further Reading