Neurotrophins promote neuronal survival and differentiation, but the fact that their expression is modified by neuronal activity, suggests a role in regulating synapse development and plasticity. In developing hippocampus, the expression of brain derived neurotrophic factor (BDNF) and its receptor TrkB increases in parallel with the ability to undergo long-term potentiation (LTP). Here we report a mechanism by which BDNF modulates hippocampal LTP. Exogenous BDNF promoted the induction of LTP by tetanic stimulation in young (postnatal day 12-13) hippocampal slices, which in the absence of BDNF show only short-term potentiation (STP). This effect was due to an enhanced ability of hippocampal synapses to respond to tetanic stimulation, rather than to a direct modulation of the LTP-triggering mechanism. A TrkB-IgG fusion protein, which scavenges endogenous BDNF, reduced the synaptic responses to tetanus as well as the magnitude of LTP in adult hippocampus. Our results suggest that BDNF may regulate LTP in developing and adult hippocampus by enhancing synaptic responses to tetanic stimulation.

Neurotrophins have traditionally been regarded as slowly acting signals essential for neuronal survival and differentiation. However, brain-derived neurotrophic factor and neurotrophin 3 (NT-3) have recently been reported to exert an acute potentiation ofsynaptic activity at the amphibian neuromuscular junction. Little is known about the role of neurotrophins on functional synapses in the central nervous system. Here we show that NT-3 rapidly increased the frequency of spontaneous action potentials, and it synchronized excitatory synaptic activities in developing cortical neurons. Moreover, the inhibitory synaptic transmission mediated by -aminobutyric acid (GABA) subtype A receptors was found to be reduced by NT-3. Thus, the excitatory effects of NT-3 on spontaneous action potentials were attributable to a reduction of GABAergic transmission. Our findings, together with previous reports of rapid regulation of central nervous system neurotrophin expression by neuronal activity and of the role of GABAergic transmission in cortical plasticity, suggest a mechanism for modulation of synaptic transmission and activitydependent synaptic modulation in cortical neurons.Extensive studies in the past few years have elucidated the important roles that the neurotrophins [including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4/5 (NT-4/5)] play in the development and maintenance of both peripheral and central nervous systems (for recent reviews see refs. 1 and 2). The functions of neurotrophins on distinct neuronal populations are mediated by the cellular expression of the trk family of tyrosine kinase receptors (3,4). While the effects of neurotrophins on neuronal survival and differentiation are well established, little is known about their role in synaptic development and function. Moreover, the classic view of neurotrophins stresses their long-lasting, chronic actions. However, a recent study showed that BDNF and NT-3 rapidly enhance synaptic activity at developing neuromuscular junctions in Xenopus cell culture (5). Will neurotrophins also serve as neuromodulators exerting fast regulation on synaptic activity in central nervous system (CNS) neurons?Neurotrophins and their receptors, the trk tyrosine kinases, are widely expressed in the brain (6-12). The fact that the expression of neurotrophins is rapidly enhanced by neuronal activity in CNS (13-22) suggests their role in activity-dependent processes, such as synaptic development and plasticity. In the present study, we sought to examine the acute effects of NT-3 on developing cortical synapses in culture, using electrophysiological approaches. We now provide direct evidence that NT-3 specifically enhances impulse activity in neurons derived from somoatosensory cortex and induces synchronization of excitatory synaptic currents. Moreover, the potentiation of neuronal activity appears to be attributable to a reduction of yaminobutyric acid (GABA)ergic synaptic transmission. Our results support the ...

Frequenin was originally identified in Drosophila melanogaster as a Ca2+-binding protein facilitating transmitter release at the neuromuscular junction. We have cloned the Xenopus frequenin (Xfreq) by PCR using degenerate primers combined with low-stringency hybridization. The deduced protein has 70% identity with Drosophila frequenin and about 38-58% identity with other Ca2+-binding proteins. The most prominent features are the four EF-hands, Ca2+-binding motifs. Xfreq mRNA is abundant in the brain and virtually nondetectable from adult muscle. Western blot analysis indicated that Xfreq is highly concentrated in the adult brain and is absent from nonneural tissues such as heart and kidney. During development, the expression of the protein correlated well with the maturation of neuromuscular synapses. To determine the function of Xfreq at the developing neuromuscular junction, the recombinant protein was introduced into Xenopus embryonic spinal neurons by early blastomere injection. Synapses made by spinal neurons containing exogenous Xfreq exhibited a much higher synaptic efficacy. These results provide direct evidence that frequenin enhances transmitter release at the vertebrate neuromuscular synapse and suggest its potential role in synaptic development and plasticity.A large number of Ca2+-binding proteins have been identified in the nervous system (1). However, the functions of these proteins are largely unknown. Recently, a Ca2+-binding protein called frequenin was cloned from Drosophila melanogaster (2). Sequence analysis indicated that the protein has a high degree of homology with the vertebrate "EF-hand" family of Ca2+-binding proteins. Transgenic flies over-expressing frequenin showed an enhanced, frequency-dependent facilitation of transmitter release at neuromuscular junctions. Thus, paired-pulse facilitation was significantly enhanced, and highfrequency stimulation gave rise to much larger postsynaptic responses (2, 3). However, the quantal content was the same in normal and transgenic flies when their motor neurons were stimulated at low frequency (3). Although the mechanisms by which frequenin facilitates transmitter release remain unknown, the identification of Drosophila frequenin opens a new avenue to study the role of Ca2+-binding proteins in the regulation of transmitter secretion and synaptic plasticity.Despite the advantage of the powerful genetics, the Drosophila neuromuscular system has its limitations in biochemical and electrophysiological analysis. In contrast, extensive knowledge is available for the normal development and function of the vertebrate neuromuscular junction (4), and recent advances in the characterization of synaptic vesicle proteins have provided a rich background for molecular studies of synaptic transmission and plasticity in vertebrates (5). Because of the ease of manipulating gene expression in the embryos and the available assays and parameters for specific stages of synaptogenesis, the Xenopus neuromuscular system represents a particularly suitable model...