Signaling mechanisms mediating BDNF modulation of synaptic plasticity in the hippocampus.

Although recent studies indicate that brain-derived neurotrophic factor (BDNF) plays an important role in hippocampal synaptic plasticity, the underlying signaling mechanisms remain largely unknown. Here, we have characterized the signaling events that mediate the BDNF modulation of high-frequency synaptic transmission. Mitogen-associated protein kinase (MAPK), phosphotidylinositol-3 kinase (PI3K), and phospholipase C-gamma (PLC-gamma) are the three signaling pathways known to mediate neurotrophin signaling in other systems. In neonatal hippocampal slices, application of BDNF rapidly activated MAPK and PI3K but not PLC-gamma. BDNF greatly attenuated synaptic fatigue at CA1 synapses induced by a train of high-frequency, tetanic stimulation (HFS). Inhibition of the MAPK and PI3K, but not PLC-gamma, prevented the BDNF modulation of high-frequency synaptic transmission. Neurotrophin-3 (NT-3), a close relative of BDNF, did not activate MAPK or PI3K and had no effect on synaptic fatigue in the neonatal hippocampus. Neither forskolin, which activated MAPK but not PI3 kinase, nor ciliary neurotrophic factor (CNTF), which activated PI3K but not MAPK, affected HFS-induced synaptic fatigue. Treatment of the slices with forskolin together with CNTF still had no effect on synaptic fatigue. Thus, although the activation of MAPK and PI3K is required, the two together are not sufficient to mediate the BDNF effect. Inhibition of new protein synthesis by anisomycin or cycloheximide did not prevent the BDNF effect. These data suggest that BDNF modulation of high-frequency transmission is independent of protein synthesis but requires MAPK and PI3K and yet another signaling pathway to act together in the hippocampus.

Presynaptic modulation of synaptic transmission and plasticity by brain-derived neurotrophic factor in the developing hippocampus.

In addition to the regulation of neuronal survival and differentiation, neurotrophins may play a role in synapse development and plasticity. Application of brain-derived neurotrophic factor (BDNF) promotes long-term potentiation (LTP) in CA1 synapses of neonatal hippocampus, which otherwise exhibit only short-term potentiation. This is attributable, at least in part, to an attenuation of the synaptic fatigue induced by high-frequency stimulation (HFS). However, the prevention of synaptic fatigue by BDNF could be mediated by an attenuation of synaptic vesicle depletion from presynaptic terminals and/or a reduction of the desensitization of postsynaptic receptors. Here we provide evidence supporting a presynaptic effect of BDNF. The effect of BDNF on synaptic fatigue depended on the stimulation frequency, not on the stimulus duration nor on the number of stimulation pulses. BDNF was only effective when the synapses were stimulated at frequencies >50 Hz. Treatment with BDNF also potentiated paired-pulse facilitation (PPF), a parameter reflecting changes in the properties of presynaptic terminals. This effect of BDNF was restricted only to PPF elicited with interpulse intervals

Recent progress in studies of neurotrophic factors and their clinical implications.

Neurotrophic factors are endogenous soluble proteins that regulate long-term survival and differentiation of neurons of the peripheral and central nervous systems. These factors play an important role in the structural integrity of the nervous system, and therefore are good candidates as therapeutic agents for neurodegenerative diseases. However, recent studies have revealed some unexpected, novel roles of neurotrophic factors. Of particular significance is the discovery of the new functions of brain-derived neurotrophic factor (BDNF) and glia-derived neurotrophic factor (GDNF). Physiological experiments indicate that BDNF may serve as regulatory factors for synaptic transmission as well as for learning and memory. Gene targeting studies demonstrate that GDNF may be essential for development of the enteric nervous system (ENS) and kidney organogenesis. These results not only provide new insights into our understanding of the function of neurotrophic factors but may also have significant implications in the therapeutic usages of neurotrophic factors.

Role of neurotrophins in synapse development and plasticity.

Neurotrophic factors are traditionally viewed as secretory proteins that regulate long-term survival and differentiation of neurons. The role of neurotrophic factors in the structural integrity of the nervous system makes them attractive candidates as therapeutic agents for neurodegenerative diseases. However, the fact that expression of many neurotrophic factors in the central nervous system is rapidly enhanced by neuronal activity suggests a new role for these factors in activity-dependent processes, such as synaptic development and plasticity. A series of recent studies has provided strong evidence for this novel function of neurotrophic factors. The neurotrophin family of proteins has been shown to acutely potentiate synaptic transmission at the neuromuscular junction and in the brain. These factors are also involved in the maturation of the neuromuscular synapses and in the development of synapses in the visual system. Gene targeting and physiological experiments demonstrate that brain-derived neurotrophic factor (BDNF) plays an important role in long-term potentiation (LTP), a cellular model for learning and memory. These findings have brought together two hotly pursued areas of neuroscience, namely, the function of neurotrophic factors and the mechanisms for synaptic plasticity. Continuous studies in this new field will help understand how synapses develop and function in the brain, and may have significant implications in treating learning disorders in both children and adults.

Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus.

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.

Heterosynaptic interactions between LTP and LTD in CA1 hippocampal slices.

Experiments in which several high and/or low frequency stimulation patterns were applied to different groups of afferents in CA1 hippocampal slices revealed the existence of heterosynaptic interactions between LTP and LTD. Specifically, we report that repeated induction of LTD on one input was associated with a heterosynaptic reversal of the LTP previously induced on a separate pathway. Reapplication of high frequency stimulation at the end of the experiment reinstated LTP. This heterosynaptic reversal occurred without modification of naive responses, and it was prevented by D-AP5, an NMDA receptor antagonist, or cyclosporin A, a calcineurin inhibitor. Similarly, induction of LTP on one input was found to reverse heterosynaptically the LTD previously induced on a separate pathway. This effect was also sensitive to D-AP5, it occurred without modification of naive pathways, and LTD could be reinstated by low frequency trains. These results indicate that repeated induction of LTP or LTD on one group of afferents can reset synaptic efficacy at other nonactivated synapses.

An amino-terminal fragment peptide of acidic fibroblast growth factor modulates synaptic transmission in rat hippocampal slices.

Effects of acidic fibroblast growth factor (aFGF) fragments such as aminoterminal aFGF (1-15) and carboxyl-terminal aFGF (114-140) on synaptic transmission were investigated in rat hippocampal slices. Stimulation was applied to Schaffer collateral/commissural afferents, and evoked population spikes were recorded in the CA1 pyramidal cell layer. Continuous perfusion of slices with aFGF (1-15) slightly decreased the basal amplitude of population spikes and significantly increased the paired-pulse facilitation. When brief tetanic stimulation (7 pulses at 100 Hz) was applied 30 min after the perfusion of aFGF (1-15), aFGF (1-15)-treated slices enhanced the magnitude of short-term potentiation after the tetanus and facilitated a generation of long-term potentiation. These effects of aFGF (1-15) were dose-dependent. Perfusion of slices with aFGF (114-140) had no effect on the basal spike amplitude, paired-pulse facilitation, and short-term potentiation. Both aFGF (1-15) and aFGF (114-140) had no effect on the DNA synthesis-stimulating activity in BALB/c 3T3-L1 cells. The results suggest that aFGF (1-15), which is not involved in mitogenic activity, is implicated in a modulatory mechanism of synaptic plasticity.

Hippocampal long-term potentiation and neural cell adhesion molecules L1 and NCAM.

Synaptic membranes express cell adhesion molecules. Here we investigate the role of the neural cell adhesion molecules L1 and NCAM in hippocampal long-term potentiation (LTP), a sustained-use-dependent increase in synaptic efficacy that has been implicated in learning and memory. L1 and NCAM mediate cell interactions during neural development and are strongly expressed in the hippocampus. They cooperate to strengthen L1-dependent cell adhesion and are coupled to second messenger pathways. We show that LTP in CA1 neurons of rat hippocampal slices was reduced by application of various L1 and NCAM antibodies, recombinant L1 fragments, and upon dissociation of the L1/NCAM complex through oligomannosidic carbohydrates and NCAM peptides. Neither the activation of NMDA (N-methyl-D-aspartate) receptors nor the maintenance of LTP was affected. These results suggest that L1 and NCAM modulate the development or the stabilization of LTP.

Acidic fibroblast growth factor facilitates generation of long-term potentiation in rat hippocampal slices.

In the present study, effects of acidic fibroblast growth factor (aFGF, 0.5-2.5 ng/ml) on synaptic transmission were investigated in rat hippocampal slices. Stimulation was applied to Schaffer collateral/commissural afferents and evoked spikes were recorded in CA1 pyramidal cell layer. Continuous perfusion of slices with aFGF slightly decreased the basal amplitude of the spikes and significantly increased the paired-pulse facilitation. When brief tetanic stimulation (7 impulses at 100 Hz) was applied 30 min after the perfusion of aFGF, aFGF-treated slices enhanced the magnitude of short-term potentiation after the tetanus and facilitated the generation of long-term potentiation. aFGF also enhanced post-tetanic potentiation directly after the tetanus. These effects of aFGF were dose-dependent. The enhancement of short-term potentiation and facilitation of the generation of long-term potentiation were not evident when aFGF was applied with or 10 min after the tetanus. The results suggest that aFGF is implicated in modulation of synaptic efficacy and can activate some mechanisms related to the generation of long-term potentiation.

Enhancement of AMPA-mediated synaptic transmission by the protein phosphatase inhibitor calyculin A in rat hippocampal slices.

Using the phosphatase inhibitor calyculin A, we have examined the influence of phosphorylation on synaptic transmission and plasticity in rat CA1 hippocampal slices. Bath application of 0.5-1 microM of calyculin A resulted in an increase of 42.6 +/- 2.9% in synaptic responses. The effect produced by calyculin A was not accompanied by changes in fibre volley, was not associated with changes in paired-pulse facilitation, and could be reproduced by intracellular injection of the compound, thereby indicating a postsynaptic action. Also, the synaptic enhancement produced by calyculin A was expressed only by potentials mediated by amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, but not by the NMDA responses recorded in the presence of the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and low magnesium. The effect of calyculin A could be prevented by KN-62, an inhibitor of calcium/calmodulin-dependent protein kinase II. Long-term potentiation could still be induced in the presence of calyculin A, but the effect of the compound was slightly reduced on potentiated compared with control pathways. These results indicate that calyculin A can selectively increase the efficacy of AMPA receptor-mediated synaptic transmission at excitatory synapses.

Long-term potentiation and depression in the ventral horn of rat spinal cord in vitro.

The aim of this study was to see whether long-term potentiation (LTP) and/or long-term depression (LTD) of synaptic efficacy could be induced in the ventral horn of the rat spinal cord. Transverse slices were cut from neonatal rat spinal cords and maintained in vitro. Field potentials were recorded in the ventral horn in response to stimulation of the dorsal horn-intermediate nucleus region of the slice. Tetanic stimulation at 100 Hz (6 bursts of 50 pulses with 10 s between bursts) resulted in long-term potentiation in 25% of slices, long-term depression in 33% of slices and no long-lasting change of field potential amplitude in the rest. The long-term changes lasted at least 2.5 hours. The principal conclusion of the work is that LTP and LTD can be elicited in the ventral horn.

[Participation of beta-endorphins in organizing neuronal activity of the rabbit hypothalamic "hunger centers"]. / Uchastie beta-éndorfina v organizatsii impul'snoi aktivnosti neironov "tsentrov goloda" gipotalamusa krolikov.

Microiontophoretic application of beta-endorphin activated neuronal activity (48%) rather than inhibited it (38%) or had no effect whatsoever (14%) in the later hypothalamus of satiated rabbits. Naloxone inhibited the neuronal activity in 75% of the cases as well as activated it (25%), no areactive neurons having been found. The variations of latency of the interspike intervals due to the effect of beta-endorphin depended on the background activity of the neurons. The beta-endorphin--sensitive neurons seem to play a part both in neuronal mechanisms of feeding motivation and in those of satiation.