Neurotrophin molecules have been used by numerous investigators to encourage regeneration of damaged spinal axons in models of spinal cord injury. However, these molecules also have short and long term effects on the strength of synaptic connections in the brain. This action is important to understand in the context of encouraging recovery of function using neurotrophins since many neurons and their axons passing through the injury zone survive the contusion which is the most common form of spinal cord injury. Neurotrophins might help strengthen these useful connections, but on the other hand they could strengthen connections responsible for damaging side effects, e.g., pain. We are proposing to continue studies of neurotrophin action on synaptic transmission focusing on determining mechanisms underlying acute (short term) and chronic (long term) effects of neurotrophins on synaptic efficacy. We use the motoneuron and its synaptic inputs as our test system because of the availability of 2 synaptic inputs that can be studied in the same cell. These connections mature at different times, and this has been very helpful in demonstrating in neonatal rats that the acute effects of neurotrophins on AMPA/kainate transmission has a strong dependence on the availability of functional NMDA receptors on the motoneuron associated with that synaptic input. We will determine whether the long lasting chronic effect is simply an extension of the acute effect or involves a different mechanism. We will also extend these studies to adults where NMDA receptors in motoneurons exhibit a substantial decline in function compared to neonates;do neurotrophins still elicit short and long term effects on synaptic transmission in adults? We will determine directly whether NMDA receptors participate directly in the maturation of AMPA/kainate receptor- mediated responses in the motoneuron. Finally, we will follow up on some recent work indicating NMDA receptor mobility in motoneurons of neonates that declines as the rat matures. We are interested in exploring whether NMDA receptor mobility is an important requirement for plasticity of synaptic connections on motoneurons. These studies have application to synaptic transmission, synaptic development and synaptic plasticity. They are expected to contribute to continued efforts to promote recovery from spinal cord injury.
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