Trans-synaptic Eph receptor-ephrin signaling in hippocampal mossy fiber LTP

The site of induction of long-term potentiation (LTP) at mossy fiber-CA3 synapses in the hippocampus is unresolved, with data supporting both pre- and postsynaptic mechanisms. Here we report that mossy fiber LTP was reduced by perfusion of postsynaptic neurons with peptides and antibodies that interfere with binding of EphB receptor tyrosine kinases (EphRs) to the PDZ protein GRIP. Mossy fiber LTP was also reduced by extracellular application of soluble forms of B-ephrins, which are normally membrane-anchored presynaptic ligands for the EphB receptors. The application of soluble ligands for presynaptic ephrins increased basal excitatory transmission and occluded both tetanus and forskolin-induced synaptic potentiation. These findings suggest that PDZ interactions in the postsynaptic neuron and trans-synaptic interactions between postsynaptic EphB receptors and presynaptic B-ephrins are necessary for the induction of mossy fiber LTP.     

Comparison of two forms of long-term potentiation in single hippocampal neurons

In invertebrate nervous systems, some long-lasting increases in synaptic efficacy result from changes in the presynaptic cell. In the vertebrate nervous system, the best understood long-lasting change in synaptic strength is long-term potentiation (LTP) in the CA1 region of the hippocampus. Here the process is initiated postsynaptically, but the site of the persistent change is unresolved. Single CA3 hippocampal pyramidal cells receive excitatory inputs from associational-commissural fibers and from the mossy fibers of dentate granule cells and both pathways exhibit LTP. Although the induction of associational-commissural LTP requires in the postsynaptic cell N-methyl-D-aspartate (NMDA) receptor activation, membrane depolarization, and a rise in calcium, mossy fiber LTP does not. Paired-pulse facilitation, which is an index of increased transmitter release, is unaltered during associational-commissural LTP but is reduced during mossy fiber LTP. Thus, both the induction and the persistent change may be presynaptic in mossy fiber LTP but not in associational-commissural LTP.     

Control of glutamate clearance and synaptic efficacy by glial coverage of neurons

Analysis of excitatory synaptic transmission in the rat hypothalamic supraoptic nucleus revealed that glutamate clearance and, as a consequence, glutamate concentration and diffusion in the extracellular space, is associated with the degree of astrocytic coverage of its neurons. Reduction in glutamate clearance, whether induced pharmacologically or associated with a relative decrease of glial coverage in the vicinity of synapses, affected transmitter release through modulation of presynaptic metabotropic glutamate receptors. Astrocytic wrapping of neurons, therefore, contributes to the regulation of synaptic efficacy in the central nervous system.     

Combined analog and action potential coding in hippocampal mossy fibers

In the mammalian cortex, it is generally assumed that the output information of neurons is encoded in the number and the timing of action potentials. Here, we show, by using direct patchclamp recordings from presynaptic hippocampal mossy fiber boutons, that axons transmit analog signals in addition to action potentials. Excitatory presynaptic potentials result from subthreshold dendritic synaptic inputs, which propagate several hundreds of micrometers along the axon and modulate action potential-evoked transmitter release at the mossy fiber-CA3 synapse. This combined analog and action potential coding represents an additional mechanism for information transmission in a major hippocampal pathway.     

Habituation: regulation through presynaptic inhibition

During tail-flip escape responses of crayfish, synaptic transmission at the habituation-prone synapses of the lateral giant reflex pathway is presynaptically inhibited. This prevents transmitter release and all subsequent postsynaptic actions and spares the reflex from becoming habituated to stimuli produced by an animal's own escape movements. These observations demonstrate the existence of a control circuit whose adaptive function is to regulate the malleability of inherently plastic synapses. They also suggest that regulation of plasticity could be a common use of presynaptic inhibition.     

Retrograde signaling by Syt 4 induces presynaptic release and synapse-specific growth

The molecular pathways involved in retrograde signal transduction at synapses and the function of retrograde communication are poorly understood. Here, we demonstrate that postsynaptic calcium 2+ ion (Ca2+) influx through glutamate receptors and subsequent postsynaptic vesicle fusion trigger a robust induction of presynaptic miniature release after high-frequency stimulation at Drosophila neuromuscular junctions. An isoform of the synaptotagmin family, synaptotagmin 4 (Syt 4), serves as a postsynaptic Ca2+ sensor to release retrograde signals that stimulate enhanced presynaptic function through activation of the cyclic adenosine monophosphate (cAMP)-cAMP-dependent protein kinase pathway. Postsynaptic Ca2+ influx also stimulates local synaptic differentiation and growth through Syt 4-mediated retrograde signals in a synapse-specific manner.     

Tetraethylammonium ions: effect of presynaptic injection on synaptic transmission

Tetraethylammonium ions were injected into the presynaptic axon of the squid giant synapse. Injection of these ions caused prolongation of the action potential with decreased out ward current. The prolonged spike was associated with increased release and prolonged activity of the transmitter substance. Although the amplitude of the postsynaptic potential increased with presynaptic depolarization, strong depolarization blocked transmitter re lease. In the injected presynaptic axon, transmitter release was blocked by 10(-6) gram of tetrodotoxin per milliliter. Transmitter release appears to be under control of presynaptic potential levels.     

Long-term facilitation in Aplysia involves increase in transmitter release

In a variety of vertebrates and invertebrates, long-lasting enhancement of synaptic transmission contributes to the storage of memory lasting one or more days. However, it has not been demonstrated directly whether this increase in synaptic transmission is caused by an enhancement of transmitter release or an increase in the sensitivity of the postsynaptic receptors. These possibilities can be distinguished by a quantal analysis in which the size of the miniature excitatory postsynaptic potential released spontaneously from the presynaptic terminal is used as a reference. By means of microcultures, in which single sensory and motor neurons of Aplysia were plated together, miniature excitatory postsynaptic potentials attributable to the spontaneous release of single transmitter quanta from individual presynaptic neurons were recorded and used to analyze long-term facilitation induced by repeated applications of 5-hydroxytryptamine. The results indicate that the facilitation is caused by an increase in the number of transmitter quanta released by the presynaptic neuron.     

Postnatal modification of hippocampal circuitry alters avoidance learning in adult rats

In rats and mice, the genetically mediated extent of the mossy fiber projection that synapses on the basal dendrites of hippocampal pyramidal cells is inversely correlated with rate of two-way avoidance (shuttle-box) learning. Postnatal hyperthyroidism, induced in 51 rat pups, resulted in marked variations of this infrapyramidal mossy fiber projection. The number of trials required for criterion performance of these rats in adulthood remained correlated with the neuroanatomical trait (r = 0.74, P less than 0.0001).     

Postsynaptic signaling and plasticity mechanisms

In excitatory synapses of the brain, specific receptors in the postsynaptic membrane lie ready to respond to the release of the neurotransmitter glutamate from the presynaptic terminal. Upon stimulation, these glutamate receptors activate multiple biochemical pathways that transduce signals into the postsynaptic neuron. Different kinds of synaptic activity elicit different patterns of postsynaptic signals that lead to short- or long-lasting strengthening or weakening of synaptic transmission. The complex molecular mechanisms that underlie postsynaptic signaling and plasticity are beginning to emerge.     

Bruchpilot promotes active zone assembly, Ca2+ channel clustering, and vesicle release

The molecular organization of presynaptic active zones during calcium influx-triggered neurotransmitter release is the focus of intense investigation. The Drosophila coiled-coil domain protein Bruchpilot (BRP) was observed in donut-shaped structures centered at active zones of neuromuscular synapses by using subdiffraction resolution STED (stimulated emission depletion) fluorescence microscopy. At brp mutant active zones, electron-dense projections (T-bars) were entirely lost, Ca2+ channels were reduced in density, evoked vesicle release was depressed, and short-term plasticity was altered. BRP-like proteins seem to establish proximity between Ca2+ channels and vesicles to allow efficient transmitter release and patterned synaptic plasticity.     

Astrocytes potentiate transmitter release at single hippocampal synapses

Astrocytes play active roles in brain physiology. They respond to neurotransmitters and modulate neuronal excitability and synaptic function. However, the influence of astrocytes on synaptic transmission and plasticity at the single synapse level is unknown. Ca(2+) elevation in astrocytes transiently increased the probability of transmitter release at hippocampal area CA3-CA1 synapses, without affecting the amplitude of synaptic events. This form of short-term plasticity was due to the release of glutamate from astrocytes, a process that depended on Ca(2+) and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein and that activated metabotropic glutamate receptors (mGluRs). The transient potentiation of transmitter release became persistent when the astrocytic signal was temporally coincident with postsynaptic depolarization. This persistent plasticity was mGluR-mediated but N-methyl-d-aspartate receptor-independent. These results indicate that astrocytes are actively involved in the transfer and storage of synaptic information.     

Contributions of two types of calcium channels to synaptic transmission and plasticity

In Aplysia sensory and motor neurons in culture, the contributions of the major classes of calcium current can be selectively examined while transmitter release and its modulation are examined. A slowly inactivating, dihydropyridine-sensitive calcium current does not contribute either to normal synaptic transmission or to any of three different forms of plasticity: presynaptic inhibition, homosynaptic depression, and presynaptic facilitation. This current does contribute, however, to a fourth form of plasticity--modulation of transmitter release by tonic depolarization of the sensory neuron. By contrast, a second calcium current, which is rapidly inactivating and dihydropyridine-insensitive, contributes to release elicited by the transient depolarization of an action potential and to the other three forms of plasticity.     

Mechanism of transmitter release: voltage hypothesis and calcium hypothesis

The calcium hypothesis of synaptic transmission has been challenged by experimental results using the crayfish neuromuscular junction that suggest that presynaptic depolarization can trigger transmitter release directly without calcium influx. Results from electrophysiological experiments using the same preparation do not support this voltage hypothesis, but are consistent with the calcium hypothesis. Voltage may modulate, but not elicit, transmitter release.     

Target-dependent structural changes accompanying long-term synaptic facilitation in Aplysia neurons

The mechanisms underlying structural changes that accompany learning and memory have been difficult to investigate in the intact nervous system. In order to make these changes more accessible for experimental analysis, dissociated cell culture and low-light-level video microscopy were used to examine Aplysia sensory neurons in the presence or absence of their target cells. Repeated applications of serotonin, a facilitating transmitter important in behavioral dishabituation and sensitization, produced growth of the sensory neurons that paralleled the long-term enhancement of synaptic strength. This growth required the presence of the postsynaptic motor neuron. Thus, both the structural changes and the synaptic facilitation of Aplysia sensorimotor synapses accompanying long-term behavioral sensitization can be produced in vitro by applying a single facilitating transmitter repeatedly. These structural changes depend on an interaction of the presynaptic neuron with an appropriate postsynaptic target.     

Calcium transient in presynaptic terminal of squid giant synapse: detection with aequorin

Microinjection of aequorin, a bioluminescent protein sensitive tocalcium, into the presynaptic terminal of the squid giant synapse demnonstrated an increase in intracellular calcium ion concentration during repetitive synaptic transmission. Although no light flashes synchronous with individual presynaptic : tion potentials were detected, the results are considered consistent with the hypothesis that entry of calcium into the presynaptic terminal triggers release of e synaptic transmitter substance.     

The structural organization of the readily releasable pool of synaptic vesicles

The defining morphological feature of chemical synapses is the vesicle cluster in the presynaptic nerve terminal. It has generally been assumed that vesicles closest to release sites are recruited first during nerve activity. We tested this by selectively labeling the "readily releasable" pool, those vesicles released first during physiological stimulation. The readily releasable vesicles were not clustered close to the presynaptic membrane but instead were dispersed almost randomly throughout the vesicle cluster. Thus, vesicles are not recruited according to proximity to release sites but are mobilized differently, perhaps by being peeled from the surface of the cluster.     

Peptide neurotoxins from fish-hunting cone snails

To paralyze their more agile prey, the venomous fish-hunting cone snails (Conus) have developed a potent biochemical strategy. They produce several classes of toxic peptides (conotoxins) that attack a series of successive physiological targets in the neuromuscular system of the fish. The peptides include presynaptic omega-conotoxins that prevent the voltage-activated entry of calcium into the nerve terminal and release of acetylcholine, postsynaptic alpha-conotoxins that inhibit the acetylcholine receptor, and muscle sodium channel inhibitors, the mu-conotoxins, which directly abolish muscle action potentials. These distinct peptide toxins share several common features: they are relatively small (13 to 29 amino acids), are highly cross-linked by disulfide bonds, and strongly basic. The fact that they inhibit sequential steps in neuromuscular transmission suggests that their action is synergistic rather than additive. Five new omega-conotoxins that block presynaptic calcium channels are described. They vary in their activity against different vertebrate classes, and also in their actions against different synapses from the same animal. There are susceptible forms of the target molecule in peripheral synapses of fish and amphibians, but those of mice are resistant. However, the mammalian central nervous system is clearly affected, and these toxins are thus of potential significance for investigating the presynaptic calcium channels.     

Bidirectional transmission at the rectifying electrotonic synapse: a voltage-dependent process

Rectifying properties of electrotonic synapses established by the crayfish giant motor fiber are associated with a more negative resting membrane potential in the presynaptic than in the postsynaptic side of the junction. An increased junctional conductance and bidirectional transmission are produced, with almost no delay, by inverting this polarization.     

PSD-95 involvement in maturation of excitatory synapses

PSD-95 is a neuronal PDZ protein that associates with receptors and cytoskeletal elements at synapses, but whose function is uncertain. We found that overexpression of PSD-95 in hippocampal neurons can drive maturation of glutamatergic synapses. PSD-95 expression enhanced postsynaptic clustering and activity of glutamate receptors. Postsynaptic expression of PSD-95 also enhanced maturation of the presynaptic terminal. These effects required synaptic clustering of PSD-95 but did not rely on its guanylate kinase domain. PSD-95 expression also increased the number and size of dendritic spines. These results demonstrate that PSD-95 can orchestrate synaptic development and are suggestive of roles for PSD-95 in synapse stabilization and plasticity.