We have found that neurotrophin molecules (such as NT-3) can modify function at synapses in the spinal cord of neonatal rats. Our goal is to devise strategies to make this useful in restoring function to the damaged spinal cord.

Key Personnel

Dr. Lorne M. Mendell
Dr. Victor Arvanian (formerly Viktor Arvanov)
Dr. Jeffrey Petruska
Dr. Sandra Garraway

Dr. Lorne M. Mendell

Background: Dr. Lorne M. Mendell is Distinguished Professor and Chair in the Department of Neurobiology and Behaviour at the State University of New York at Stony Brook.

Dr. Mendell was graduated from McGill University in 1961. He received his Ph.D. from MIT in 1965 working with Professor P.D. Wall on spinal mechanisms of pain. During 3 postdoctoral years in the laboratory of Dr. Elwood Henneman at Harvard Medical School he investigated the functional connectivity of individual sensory neurons in the mammalian spinal cord. In 1968 he moved to Duke University. His research there was concerned with alterations in functional synaptic connections after injury to the spinal cord, its inputs and its outputs.

In 1980 Dr. Mendell moved to the Department of Neurobiology and Behaviour at Stony Brook here he became chair in 1988. His research has broadened to include consideration of the functional role of neurotrophins on spinal neurons and synapses particularly as it applies to pain pathways, to segmental reflex function and to development and regeneration of spinal circuits (see his personal lab page). He has received 2 consecutive Jacob Javits Neuroscience Awards from NINDS for his research on Mechanisms of Neuronal Plasticity. Other honors and awards include a Research Career Development Award and a Josiah Macy Faculty Scholar Award.

Dr. Mendell has served on several editorial boards and was editor-in-chief of the Journal of Neurophysiology. He was President of the Society for Neuroscience in 1997-98. He is presently a Scientific Trustee of Cold Spring Harbor Laboratory and a member of the Repair and Plasticity Planning Committee at the NINDS.

Research Themes:

Neurotrophins are molecules that are known to stimulate cell differentiation, to encourage axonal growth and to improve survival of cells during development and when studied in culture. These characteristics have made neurotrophins candidate molecules to reverse the degenerative changes after spinal cord injury. In fact, they have been found by laboratories in this Consortium to encourage elongation of axons in the damaged spinal cord. Recent experiments in our laboratory indicate that these molecules can also enhance the transmission between neurons in the spinal cord.

The injured spinal cord is not completely devoid of function. In a contusion injury some fibers connecting the brain with spinal segments below the level of the injury may survive, and one strategy for enhancing recovery would be to increase the synaptic potency of the surviving connections. However, there is also some evidence that the action of these molecules could be counterproductive, i.e., cause some side effect such as pain that would limit their therapeutic potential or at the very least would require some countermeasure. These considerations point to the need to understand the physiological or functional effects of neurotrophin molecules. This is the focus of our laboratory which is one of the very few in the world currently studying the physiological effects of neurotrophins in the spinal cord in vivo.

In the past year we have made an important discovery concerning the function of these neurotrophins. We had previously learned that one of these neurotrophins, NT-3, normally loses its ability to influence neural connections when the rat reaches about 1 week of age. This prompted us to determine why it loses this ability. If we knew why this was so, we might be able to prevent this loss of ability and thereby make neurotrophins more useful for reversing the effects of damage in the adult spinal cord. We have found that this is indeed possible; however, the mechanism is not a practical one for the living spinal cord since it involves changing the ionic solutions normally bathing the spinal cord. There are theoretically other mechanisms to affect this function and one of them might involve increasing activity levels in spinal neurons. This may turn out to be a useful link between exercise and cellular function, and might reveal why exercise seems to have the ability to improve function of the injured spinal cord. This is one of the areas we wish to explore.

Specific experimental approaches:

We currently use 3 experimental preparations to study these questions. The spinal cord slice is valuable because it offers the opportunity to make patch clamp recordings from cells in visualized regions of the spinal cord. Thus we are presently studying the effects of neurotrophins on cells in lamina II, a region that is specialized for the processing of inputs from sensory fibers specialized to transmit information concerning damage to peripheral tissues.  We also are studying the effects of neurotrophins on motor neurons in the in vitro spinal cord (i.e., in a dish). This preparation has the advantage of preserving much of the intrinsic circuitry of the spinal cord. Both of these preparations have the disadvantage that they only work well in neonatal animals, and so we are also investigating the effect of neurotrophins in the adult spinal cord studied in vivo. 

One of the interests linking these different approaches is delivery of neurotrophins that might be potentially useful in patients. Here we are collaborating with laboratories in the Consortium to investigate engineered fibroblasts expressing neurotrophins (Gage laboratory) and viruses engineered to deliver neurotrophin genes to selected tissues (Parada laboratory). The question is whether these vectors could serve as a convenient long-term source of neurotrophins in animals and whether this could improve function of the damaged spinal cord.

2.   Mendell, L.M., Johnson, R.D. and Munson, J.B. (1999)  Neurotrophin modulation of the monosynaptic reflex after peripheral nerve transection. J. Neurosci. 19: 3162-3170. 

3.   Munson, J.B., Johnson, R.D., Mendell, L.M. (1999) Neurotrophin-3 and maintenance of muscle afferent function. Prog. Brain. Res. 123:157-163  

4.   Mendell, L.M., Albers, K.M. and Davis, B.M. (1999) Neurotrophins, Nociceptors and Pain. Microscopy Research and Technique. 45: 252-261  

5.   Shu, X. and Mendell, L.M. (1999) Nerve growth factor acutely sensitizes the response of adult rat sensory neurons to capsaicin. Neurosci. Lett. 274:159-162  

6.   Mendell, L.M. (1999) Neurotrophin action on sensory neurons in adults: An extension of the Neurotrophic Hypothesis. Pain Supplement 6: S127-S132. 

7. Mendell, L.M. and Munson, J.B. (1999) Retrograde effects on transmission at the Ia/motoneuron synapse during high frequency activation.  J. Physiol. (Paris). 93:297-304. 

8. Shu, X.-Q. and Mendell L.M. (1999) Neurotrophins and Hyperalgesia. Proceedings of the National Academy of Sciences (Suppl.) 96(14):7693-6 

9.  Arvanov, V.L., Seebach, B.S. and Mendell, L.M. (2000) NT-3 evokes an LTP- like facilitation of AMPA/Kainate- mediated synaptic transmission in the neonatal rat spinal cord.
J. Neurophysiol. 84 (2): 752-758, 2000.

10. Mendell, L.M., Munson, J.B. and Arvanov, V.L. (In Press) Neurotrophins and Synaptic Plasticity in the Mammalian Spinal Cord. 
J. Physiol. 533, 91-7, 2001.   

11.  Mendell, L.M. (In Press) Peripheral Neurotrophic factors and pain. In: Pain: Current Understanding, Emerging Therapies and Novel Approaches to Drug Discovery. Eds. C. Bountra, Munglani, R. and Schmidt, W.K. Marcel Dekker 

12. Mendell, L.M. (In Press) Nociceptors. In: Encyclopedia of the Human Brain. Ed. V.S. Ramachandran. Academic Press 

13. Arvanov, V.L. and Mendell, L.M. (In Press) Removal of NMDA receptor Mg2+ block extends the action of neurotrophin-3 on synaptic transmission in neonatal rat motoneurons. 
J. Neurophysiol. 86, 123-9, 2001. 

14. Arvanian VL & Mendell LM. Acute modulation of synaptic transmission to motoneurons by BDNF in the neonatal rat spinal cord.
Eur J Neurosci. 14:1800-8, 2001

Research Approach

Dr. Mendell and his colleagues have found that while the acute administration of Neurotrophin-3 (NT-3) enhances the synaptic function in the spinal cords of very young rats, it happens only when NMDA receptors are functionally active. In other words, the activity of NMDA receptors is required for the acute action of NT-3. For example, acute NT-3 does not affect synaptic function in older rats because their NMDA receptors are less active than those in younger animals.  Interestingly, the results of recent collaborations with the Gage laboratory using NT-3-secreting fibroblasts revealed that longer-term delivery of NT-3 to the spinal cord enhanced synaptic transmission in a descending pathway that was insensitive to the acute administration of neurotrophins.