Enhancing circuit perfomance in injured spinal cord

Dr. Lorne Mendell's talk at Emory, May 21, 2009

Smashed spinal cord
- cell death
- activity-based therapy
Encouraging functional recovery
- reducing cell death
- replace absent cells
- enhancing performance of sensory circuit
a) training
b) neurotrophine-induced synaptic potentiation

Neonatal transection: Step training can enhance stepping performance
- trained animals can walk when they grew up
- shape of the movement is slightly different (less force?)
- ankle angle

Recovery reverses transection-induced changes in monosynaptic EPSPs and AHP
- Change in population of EPSP size and AHP
a) transection reduced the overall size of EPSPs (more small EPSPs than large EPSPs)
b) shift of EPSP population to have more large EPSPs
c) much more large EPSPs than control
d) AHP became larger, but became smaller after training.

Improved stepping performance correlated with change in motoneuron
- Change in AHP depth indicates the ability to fire at high frequency
- Change in EPSP amplitude indicate changes in the sensory feedback from muscle spindle (ankle)

NT-3 (&BNDF)
- motor improvement
= both mimicked by NT-3?
- electrophysiological changes (EPSP, AHP)

NT-3 is required for motoneuronal projections to muscle spindle
Acute sensitization by NTs
- neurotrophic factor (NT-3) sensitize motoneurons.
- for example, it sensitize GluR

Chronic effects of NT-3 on the strength of the mo...

NT-3 strengthen projections of injured & developing spindle afferent to motoneurons
- intraneural NT-3 enhance synapses for axotmized neurons.

Substitute NT-3 for training
- virus that has NT-3 is injected into muscle

Delivery of neurotrophines to intact preparations without trauma: Viral vectors
- AAV/NT-3; expression, 150 days

NT-3 expression profiles differ according to the preparation, and physiological effects differ accordingly
- Cord NT-3 was plotted against DRG NT-3.
- In spinal cord, NT-3 expression is larger in the intact than transected animal.
- In the intact prep, EPSPs became smaller after transection (probably by increase of the motoneuron's size).
- Appearance of large EPSPs for transected animals (by sprouting by presynaptic afferent neurons = DRG neuron)

Input resistance of motor neuron was reduced
- by increase of the motoneuron's size
- contribute to the reduction of the EPSP size

AAV/NT-3 decreases motoneuronal input resistance
- in intact animal, it reduced both EPSP size and Rm
- in transected animal, it only reduced Rm size, but increased the EPSP size.

Ventrolateral white matter (VLF?) synapses persist on motoneurons in chronically transected preparation

Changes after AAV/NT-3 in intact preparations
- the change in EPSP size was synapse specific

Trained animals are different from AAV/NT-3 treated
- Trained animal shows both increase in Rm and EPSP size in the motoneurons.
- c-fos

AVV/NT-3 enhances the stretch-reflex by increased performance in stepping

NT-3 strengthens MG strech pathway by increased EPSP size.

- K. Pearson Exp Br Res (2003)

- Chen Y et al., 2006, JNsc26: 12537.

- Modeling stepping function by a model: Yakovenko et al., (2004)
Stretch reflex enhances stability of CPG circuit

Neurotropin treatment of adult transected preparations (preliminary results).