Although neurotrophins have traditionally been regarded as neuronal survival factors, recent work has suggested a role for these factors in synaptic plasticity. In particular, brain-derived neurotrophic factor (BDNF) rapidly enhances synaptic transmission in hippocampal neurons through trkB receptor stimulation and postsynaptic phosphorylation mechanisms. Activation of trkB also modulates hippocampal long-term potentiation, in which postsynaptic N-methyl-D-aspartate glutamate receptors play a key role. However, the final common pathway through which BDNF increases postsynaptic responsiveness is unknown. We now report that BDNF, within 5 min of exposure, elicits a dosedependent increase in phosphorylation of the N-methyl-Daspartate receptor subunit 1. This acute effect occurred in hippocampal synaptoneurosomes, which contain pre-and postsynaptic elements, and in isolated hippocampal postsynaptic densities. Nerve growth factor, in contrast, caused no enhancement of phosphorylation. These results suggest a potential mechanism for trophin-induced potentiation of synaptic transmission.Neurotrophins play important roles in the survival and differentiation of specific neuronal populations during development and adulthood (1-3). Four members of the mammalian neurotrophin gene family have been identified: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and NT-4͞5 (4, 5). The neurotrophins bind to receptor tyrosine kinases of the trk protooncogene family with high affinity. trkA is a high-affinity receptor for NGF (6, 7), trkB for BDNF and NT-4͞5 (8, 9) as well as NT-3 (10), and trkC for .In addition to classical trophic activities, we and others have shown that neurotrophins acutely modulate synaptic transmission (12-19) and long-term potentiation (20). Experiments with dissociated cultures of hippocampal neurons indicate that BDNF and NT-4͞5 rapidly and selectively potentiate excitatory synaptic currents (17-19), and this trkB-mediated synaptic enhancement involves phosphorylation-dependent modulation of postsynaptic responsiveness (18). The exact mechanisms by which trkB activation modulates synaptic transmission remain to be established.We recently found that trkB is a functionally active, intrinsic component of the adult rat postsynaptic density (PSD) isolated from cerebral cortex and hippocampus (21). The PSD is a proteinaceous disc-shaped subcellular organelle apposed to the inner surface of the postsynaptic membrane of chemical synapses (22). Neurotransmitter receptors, protein kinases, and ion channel proteins are anchored to the PSD (22), suggesting that the PSD participates in signal transduction and even receptor regulation. In fact, our recent studies revealed that N-methyl-D-aspartate (NMDA) receptors can be phosphorylated by intrinsic PSD kinases (23,24). Phosphorylation of NMDA receptors is known to enhance receptor binding, channel conductance, and synaptic transmission (25-27). Because trkB activation enhances synaptic activity via postsynaptic phosphor...

Duchenne muscular dystrophy (DMD) is a common, lethal, chromosome X-linked inherited disease. Moderate cognitive airment is a feature of DMD, but the underlying mecaisms are unknown. DMD is cra d by a defect in a protein,, dystrophin, that is located pdominamtly in muscle but has been dtecled in brain. We sought to dlrectiy localize dystophn within the complex synaptic structure of the cerebral cortex by fin on the postsynaptic density (PSD), which appears to be central to Fyaplcfamction.We report that a specific anti-dystrophin antibody (anti 6-10) recognizes three distinct proteins In the purified PSD: the 400-kDa dystrophin and two previously u fied dystrophin-related proteins of 120 and 110 kDa. These proteins exhibited differential r exprsin in PSDs from cerebral cortex, cerebellum, and olfactory bulb. In the cortical PSD, the 400-kDa dystrophin was predominant, whereas the 120-kDa protein was the major species In cerl and olfactory bulb PSDs. The three proteins were differentially expressed in the PSD during cortical development: the 4W0-kDa protein exhibited a selective 9-fold inase during po days 7 to 10, suggesting a normal physiological role in synaptic maturation. The PSD from the mdx mouse, a model of human DMD, contained no detctable 400-kDa dystrophin but expressed the two dphin-related proteins. Our results indicate that brain dystrophins are laled to the PSD, potentially as three isoforms, and raise the possibility that cognitive abnormalities in DMD are attributable to synaptic dy on associated with deficits in brain dystopin molecules.Duchenne muscular dystrophy (DMD) is a common, lethal, chromosome X-linked inherited disease affecting 1 in 3500 boys (for review, see ref.

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