NT-3 Evokes an LTP-Like Facilitation of AMPA/Kainate Receptor–Mediated Synaptic Transmission in the Neonatal Rat Spinal Cord

Abstract

Neurotrophin-3 (NT-3) is a neurotrophic factor required for survival of muscle spindle afferents during prenatal development. It also acts postsynaptically to enhance the monosynaptic excitatory postsynaptic potential (EPSP) produced by these fibers in motoneurons when applied over a period of weeks to the axotomized muscle nerve in adult cats. Similar increases in the amplitude of the monosynaptic EPSP in motoneurons are observed after periodic systemic treatment of neonatal rats with NT-3. Here we show an acute action of NT-3 in enhancing the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA/kainate) receptor–mediated fast monosynaptic EPSP elicited in motoneurons by dorsal root (DR) stimulation in the in vitro hemisected neonatal rat spinal cord. The receptor tyrosine kinase inhibitor K252a blocks this action of NT-3 as does the calcium chelator bis-( o-aminophenoxy)- N, N, N′, N′-tetraacetic acid (BAPTA) injected into the motoneuron. The effect of NT-3 resembles long-term potentiation (LTP) in that transient bath application of NT-3 to the isolated spinal cord produces a long-lasting increase in the amplitude of the monosynaptic EPSP. An additional similarity is that activation of N-methyl-d-aspartate (NMDA) receptors is required to initiate this increase but not to maintain it. The NMDA receptor blocker MK-801, introduced into the motoneuron through the recording microelectrode, blocks the effect of NT-3, indicating that NMDA receptors in the motoneuron membrane are crucial. The effect of NT-3 on motoneuron NMDA receptors is demonstrated by its enhancement of the depolarizing response of the motoneuron to bath-applied NMDA in the presence of tetrodotoxin (TTX). The potentiating effects of NT-3 do not persist beyond the first postnatal week. In addition, EPSPs with similar properties evoked in the same motoneurons by stimulation of descending fibers in the ventrolateral funiculus (VLF) are not modifiable by NT-3 even in the initial postnatal week. Thus, NT-3 produces synapse-specific and age-dependent LTP-like enhancement of AMPA/kainate receptor–mediated synaptic transmission in the spinal cord, and this action requires the availability of functional NMDA receptors in the motoneuron.