Neurotrophins are important secreted factors which regulate neuronal survival during development. In recent years it has been found that the newer members of this family, BDNF, NT-3 and NT-4 are can rapidly modulating synaptic efficacy at peripheral and central synapses (Berninger and Poo, 1996; Lewin and Barde, 1996). In this application we will investigate the role of pre-synaptically releases BDNF on the physiological status of primary afferent to spinal cord synapses in mutant mice. Using an in vitro spinal cord preparration from mutant mice the ability of C-fibers nociceptors to induce homo- and heterosynaptic facilitation of the ventral root reflex will be tested. Recently, we have characterized a trk B knock-in mouse where the Shc adaptor proteins cannot bind to the activated kinase receptor. These mice resemble closely NT-4 knockouts in the peripheral nervous system (Minichiello et al. 1998). We want to see if BDNF or NT-4 stimulation of the trk B receptors not signaling via Shc can produce central sensitzation in the spinal cord. In addition we are continuing to develop the gene gun as a device to reintroduce cDNAs of interest into post-mitotic neurons in situ. In addition we will in the next year examine a BDNF promotor knockout where we hope the expression of BDNF is selectively reduced in the peripheral nervous system.
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