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Eric R. Kandel - One of the best experts on this subject based on the ideXlab platform.
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Presynaptic inhibition in aplysia involves a decrease in the ca2 current of the Presynaptic Neuron transmitter release modulation voltage clamp
2016Co-Authors: Eli Shapiro, Vincent F. Castellucci, Eric R. KandelAbstract:By voltage clamping Presynaptic cell L1O and using pharmacologic separation techniques, we have analyzed the specific ionic currents in the Presynaptic cell that correlate with Presynaptic inhibition while assaying transmitter release with intracellular recordings from postsynaptic cells. We have found that Presynaptic inhibition can be elicited in conditions in which the Na+ and the various K+ channels are pharmaco- logically blocked and depolarizing current pulses produce only an inward Ca2+ current. Both inward currents and tail currents at and above the K+ reversal potential were always less inward during Presynaptic inhibition. The changes in conductance associated with Presynaptic inhibition were voltage sensitive and paralleled the voltage sensitivity of the Ca2+ channel. We therefore conclude that Presynaptic inhibition is caused by a direct transmitter-mediated decrease of Presynaptic Ca2+_ channel conductance.
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spontaneous transmitter release recruits postsynaptic mechanisms of long term and intermediate term facilitation in aplysia
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Joseph B Rayman, Eric R. Kandel, Sathya Puthanveettil, Robert D HawkinsAbstract:Whereas short-term (minutes) facilitation at Aplysia sensory–motor Neuron synapses is Presynaptic, long-term (days) facilitation involves synaptic growth, which requires both Presynaptic and postsynaptic mechanisms. How are the postsynaptic mechanisms recruited, and when does that process begin? We have been investigating the possible role of spontaneous transmitter release from the Presynaptic Neuron. In the previous paper, we found that spontaneous release is critical for the induction of long-term facilitation, and this process begins during an intermediate-term stage of facilitation that is the first stage to involve postsynaptic as well as Presynaptic mechanisms. We now report that increased spontaneous release during the short-term stage acts as an orthograde signal to recruit postsynaptic mechanisms of intermediate-term facilitation including increased IP3, Ca2+, and membrane insertion and recruitment of clusters of AMPA-like receptors, which may be first steps in synaptic growth during long-term facilitation. These results suggest that the different stages of facilitation involve a cascade of pre- and postsynaptic mechanisms, which is initiated by spontaneous release and may culminate in synaptic growth.
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spontaneous transmitter release is critical for the induction of long term and intermediate term facilitation in aplysia
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Sathya Puthanveettil, Eric R. Kandel, Kevin A Karl, Robert D HawkinsAbstract:Long-term plasticity can differ from short-term in recruiting the growth of new synaptic connections, a process that requires the participation of both the Presynaptic and postsynaptic components of the synapse. How does information about synaptic plasticity spread from its site of origin to recruit the other component? The answer to this question is not known in most systems. We have investigated the possible role of spontaneous transmitter release as such a transsynaptic signal. Until recently, relatively little has been known about the functions of spontaneous release. In this paper, we report that spontaneous release is critical for the induction of a learning-related form of synaptic plasticity, long-term facilitation in Aplysia. In addition, we have found that this signaling is engaged quite early, during an intermediate-term stage that is the first stage to involve postsynaptic as well as Presynaptic molecular mechanisms. In a companion paper, we show that spontaneous release from the Presynaptic Neuron acts as an orthograde signal to recruit the postsynaptic mechanisms of intermediate-term facilitation and initiates a cascade that can culminate in synaptic growth with additional stimulation during long-term facilitation. Spontaneous release could make a similar contribution to learning-related synaptic plasticity in mammals.
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NITRIC OXIDE ACTS DIRECTLY IN THE Presynaptic Neuron TO PRODUCE LONG-TERM POTENTIATION IN CULTURED HIPPOCAMPAL NeuronS
Cell, 1996Co-Authors: Ottavio Arancio, Michael A. Kiebler, C. Justin Lee, Varda Lev-ram, Roger Y. Tsien, Eric R. KandelAbstract:Nitric oxide (NO) has been proposed to act as a retrograde messenger during long-term potentiation (LTP) in the CA1 region of hippocampus, but the inaccessibility of the Presynaptic terminal has prevented a definitive test of this hypothesis. Because both sides of the synapse are accessible in cultured hippocampal Neurons, we have used this preparation to investigate the role of NO. We examined LTP following intra- or extracellular application of an NO scavenger, an inhibitor of NO synthase, and a membrane-impermeant NO donor that releases NO only upon photolysis with UV light. Our results indicate that NO is produced in the postsynaptic Neuron, travels through the extracellular space, and acts directly in the Presynaptic Neuron to produce long-term potentiation, supporting the hypothesis that NO acts as a retrograde messenger during LTP.
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activity dependent long term enhancement of transmitter release by Presynaptic 3 5 cyclic gmp in cultured hippocampal Neurons
Nature, 1995Co-Authors: Ottavio Arancio, Eric R. Kandel, R D HawkinsAbstract:LONG–TERM potentiation (LTP) in hippocampus is a type of synap-tic plasticity that is thought to be involved in learning and memory1. Several lines of evidence suggest that LTP involves 3′,5′-cyclic GMP (cGMP), perhaps as an activity-dependent Presynaptic effector of one or more retrograde messengers (refs 2-12, but see ref. 13). However, previous results are also consistent with postsynaptic effects of cGMP. This is difficult to test in hippocam-pal slices, but more rigorous tests are possible in dissociated cell culture14–17. We have therefore developed a reliable method for producing N-methyl-D-aspartate (NMDA) receptor-dependent LTP at synapses between individual hippocampal pyramidal Neurons in culture. We report that inhibitors of guanylyl cyclase or of cGMP-dependent protein kinase block potentiation by either tetanic stimulation or low-frequency stimulation paired with postsynaptic depolarization. Conversely, application of 8-Br-cGMP to the bath or injection of cGMP into the Presynaptic Neuron produces activity-dependent long-lasting potentiation. The potentiation by cGMP involves an increase in transmitter release that is in part independent of changes in the Presynaptic action potential. These results support a Presynaptic role for cGMP in LTP.
Robert D Hawkins - One of the best experts on this subject based on the ideXlab platform.
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spontaneous transmitter release recruits postsynaptic mechanisms of long term and intermediate term facilitation in aplysia
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Joseph B Rayman, Eric R. Kandel, Sathya Puthanveettil, Robert D HawkinsAbstract:Whereas short-term (minutes) facilitation at Aplysia sensory–motor Neuron synapses is Presynaptic, long-term (days) facilitation involves synaptic growth, which requires both Presynaptic and postsynaptic mechanisms. How are the postsynaptic mechanisms recruited, and when does that process begin? We have been investigating the possible role of spontaneous transmitter release from the Presynaptic Neuron. In the previous paper, we found that spontaneous release is critical for the induction of long-term facilitation, and this process begins during an intermediate-term stage of facilitation that is the first stage to involve postsynaptic as well as Presynaptic mechanisms. We now report that increased spontaneous release during the short-term stage acts as an orthograde signal to recruit postsynaptic mechanisms of intermediate-term facilitation including increased IP3, Ca2+, and membrane insertion and recruitment of clusters of AMPA-like receptors, which may be first steps in synaptic growth during long-term facilitation. These results suggest that the different stages of facilitation involve a cascade of pre- and postsynaptic mechanisms, which is initiated by spontaneous release and may culminate in synaptic growth.
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spontaneous transmitter release is critical for the induction of long term and intermediate term facilitation in aplysia
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Sathya Puthanveettil, Eric R. Kandel, Kevin A Karl, Robert D HawkinsAbstract:Long-term plasticity can differ from short-term in recruiting the growth of new synaptic connections, a process that requires the participation of both the Presynaptic and postsynaptic components of the synapse. How does information about synaptic plasticity spread from its site of origin to recruit the other component? The answer to this question is not known in most systems. We have investigated the possible role of spontaneous transmitter release as such a transsynaptic signal. Until recently, relatively little has been known about the functions of spontaneous release. In this paper, we report that spontaneous release is critical for the induction of a learning-related form of synaptic plasticity, long-term facilitation in Aplysia. In addition, we have found that this signaling is engaged quite early, during an intermediate-term stage that is the first stage to involve postsynaptic as well as Presynaptic molecular mechanisms. In a companion paper, we show that spontaneous release from the Presynaptic Neuron acts as an orthograde signal to recruit the postsynaptic mechanisms of intermediate-term facilitation and initiates a cascade that can culminate in synaptic growth with additional stimulation during long-term facilitation. Spontaneous release could make a similar contribution to learning-related synaptic plasticity in mammals.
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rapid increase in clusters of synaptophysin at onset of homosynaptic potentiation in aplysia
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Iksung Jin, Hiroshi Udo, Robert D HawkinsAbstract:Imaging studies have shown that even the earliest phases of long-term plasticity are accompanied by the rapid recruitment of synaptic components, which generally requires actin polymerization and may be one of the first steps in a program that can lead to the formation of new stable synapses during late-phase plasticity. However, most of those results come from studies of long-term potentiation in rodent hippocampus and might not generalize to other forms of synaptic plasticity or plasticity in other brain areas and species. For example, recruitment of Presynaptic proteins during long-term facilitation by 5HT in Aplysia is delayed for several hours, suggesting that whereas activity-dependent forms of plasticity, such as long-term potentiation, involve rapid recruitment of Presynaptic proteins, neuromodulatory forms of plasticity, such as facilitation by 5HT, involve more delayed recruitment. To begin to explore this hypothesis, we examined an activity-dependent form of plasticity, homosynaptic potentiation produced by tetanic stimulation of the Presynaptic Neuron in Aplysia. We found that homosynaptic potentiation involves Presynaptic but not postsynaptic actin and a rapid (under 10 min) increase in the number of clusters of the Presynaptic vesicle-associated protein synaptophysin. These results indicate that rapid recruitment of synaptic components is not limited to hippocampal potentiation and support the hypothesis that activity-dependent types of plasticity involve rapid recruitment of Presynaptic proteins, whereas neuromodulatory types of plasticity involve more delayed recruitment.
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tests of the roles of two diffusible substances in long term potentiation evidence for nitric oxide as a possible early retrograde messenger
Proceedings of the National Academy of Sciences of the United States of America, 1991Co-Authors: Thomas J Odell, Eric R. Kandel, Robert D Hawkins, Ottavio ArancioAbstract:Abstract Although long-term potentiation (LTP) in the CA1 region of the hippocampus is initiated postsynaptically by the influx of Ca2+ through N-methyl-D-aspartate receptor channels, the maintenance of LTP seems to be at least in part Presynaptic. This suggests that the postsynaptic cell releases a retrograde messenger to activate the Presynaptic terminals. It is likely that this messenger is membrane-permeant and reaches the Presynaptic Neuron by diffusion. We therefore have investigated two major membrane-permeant candidate retrograde messengers, arachidonic acid and nitric oxide (NO). Consistent with arachidonic acid or a lipoxygenase metabolite being a retrograde messenger, the phospholipase A2 and lipoxygenase inhibitor nordihydroguaiaretic acid blocked LTP in the guinea pig CA1 region in vitro. However, arachidonic acid (up to 100 microM) did not reliably produce activity-independent LTP, and activity-dependent potentiation by arachidonic acid was blocked by DL-aminophosphonovaleric acid. Since nordihydroguaiaretic acid also interferes with signal transduction involving NO, we next examined whether inhibitors of NO synthase block LTP. NG-Nitro-L-arginine blocked LTP when given in the bath, and this inhibition was partially overcome by high concentrations of L-arginine, suggesting that the inhibitor is specific to NO synthase. NG-Nitro-L-arginine and NG-methyl-L-arginine (but not NG-methyl-D-arginine) also blocked LTP when injected intracellularly, indicating that NO synthase is located in the postsynaptic cell. The NO, in turn, seems to be released into the extracellular space, since bathing the slice with hemoglobin, a protein that binds NO and is not taken up by cells, also blocked LTP. Moreover, NO enhances spontaneous Presynaptic release of transmitter from hippocampal Neurons in dissociated cell culture. These data favor the idea that NO might be a retrograde messenger in LTP.
P Somogyi - One of the best experts on this subject based on the ideXlab platform.
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quantitative localisation of synaptic and extrasynaptic gabaa receptor subunits on hippocampal pyramidal cells by freeze fracture replica immunolabelling
European Journal of Neuroscience, 2010Co-Authors: Y Kasugai, Jerome D Swinny, J D B Roberts, Y Dalezios, Yugo Fukazawa, Werner Sieghart, Ryuichi Shigemoto, P SomogyiAbstract:Hippocampal CA1 pyramidal cells, which receive γ-aminobutyric acid (GABA)ergic input from at least 18 types of Presynaptic Neuron, express 14 subunits of the pentameric GABAA receptor. The relative contribution of any subunit to synaptic and extrasynaptic receptors influences the dynamics of GABA and drug actions. Synaptic receptors mediate phasic GABA-evoked conductance and extrasynaptic receptors contribute to a tonic conductance. We used freeze-fracture replica-immunogold labelling, a sensitive quantitative immunocytochemical method, to detect synaptic and extrasynaptic pools of the alpha1, alpha2 and beta3 subunits. Antibodies to the cytoplasmic loop of the subunits showed immunogold particles concentrated on distinct clusters of intramembrane particles (IMPs) on the cytoplasmic face of the plasma membrane on the somata, dendrites and axon initial segments, with an abrupt decrease in labelling at the edge of the IMP cluster. Neuroligin-2, a GABAergic synapse-specific adhesion molecule, co-labels all beta3 subunit-rich IMP clusters, therefore we considered them synapses. Double-labelling for two subunits showed that virtually all somatic synapses contain the alpha1, alpha2 and beta3 subunits. The extrasynaptic plasma membrane of the somata, dendrites and dendritic spines showed low-density immunolabelling. Synaptic labelling densities on somata for the alpha1, alpha2 and beta3 subunits were 78–132, 94 and 79 times higher than on the extrasynaptic membranes, respectively. As GABAergic synapses occupy 0.72% of the soma surface, the fraction of synaptic labelling was 33–48 (alpha1), 40 (alpha2) and 36 (beta3)% of the total somatic surface immunolabelling. Assuming similar antibody access to all receptors, about 60% of these subunits are in extrasynaptic receptors.
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input dependent synaptic targeting of alpha 2 subunit containing gaba a receptors in synapses of hippocampal pyramidal cells of the rat
European Journal of Neuroscience, 2001Co-Authors: P Somogyi, Gabor Nyiri, Tamas F FreundAbstract:Pyramidal cells, expressing at least 14 subunits of the heteropentameric GABA(A) receptor, receive GABAergic input on their soma and proximal dendrites from basket cells, activating GABA(A) receptors and containing either parvalbumin or cholecystokinin and vasoactive intestinal polypeptide. The properties of GABA(A) receptors are determined by the subunit composition, and synaptic receptor content governs the effect of the Presynaptic Neuron. Using a quantitative electron microscopic immunogold technique, we tested whether the synapses formed by the two types of basket cell show a difference in the subunit composition of GABA(A) receptors. Terminals of one of the basket cells were identified by antibodies to parvalbumin. Synapses made by parvalbumin-negative terminals showed five times more immunoreactivity for the alpha(2) subunit than synapses made by parvalbumin-positive basket cells, whose synapses were frequently immunonegative. This difference is likely to be due to specific GABA(A) receptor alpha subunit composition, because neither synaptic size nor immunoreactivity for the beta(2/3) subunits, indicating total receptor content, was different in these two synapse populations. Synapses established by axo-axonic cells on axon initial segments showed an intermediate number of immunoparticles for the alpha(2) subunit compared to those made by basket cells but, due to their smaller size, the density of the alpha(2) subunit immunoreactivity was higher in synapses on the axon. Because the two basket cell types innervate the same domain of the pyramidal cell, the results indicate that pyramidal cells have mechanisms to target GABA(A) receptors, under Presynaptic influence, preferentially to distinct synapses. The two basket cell types act via partially distinct GABA(A) receptor populations.
Ottavio Arancio - One of the best experts on this subject based on the ideXlab platform.
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NITRIC OXIDE ACTS DIRECTLY IN THE Presynaptic Neuron TO PRODUCE LONG-TERM POTENTIATION IN CULTURED HIPPOCAMPAL NeuronS
Cell, 1996Co-Authors: Ottavio Arancio, Michael A. Kiebler, C. Justin Lee, Varda Lev-ram, Roger Y. Tsien, Eric R. KandelAbstract:Nitric oxide (NO) has been proposed to act as a retrograde messenger during long-term potentiation (LTP) in the CA1 region of hippocampus, but the inaccessibility of the Presynaptic terminal has prevented a definitive test of this hypothesis. Because both sides of the synapse are accessible in cultured hippocampal Neurons, we have used this preparation to investigate the role of NO. We examined LTP following intra- or extracellular application of an NO scavenger, an inhibitor of NO synthase, and a membrane-impermeant NO donor that releases NO only upon photolysis with UV light. Our results indicate that NO is produced in the postsynaptic Neuron, travels through the extracellular space, and acts directly in the Presynaptic Neuron to produce long-term potentiation, supporting the hypothesis that NO acts as a retrograde messenger during LTP.
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activity dependent long term enhancement of transmitter release by Presynaptic 3 5 cyclic gmp in cultured hippocampal Neurons
Nature, 1995Co-Authors: Ottavio Arancio, Eric R. Kandel, R D HawkinsAbstract:LONG–TERM potentiation (LTP) in hippocampus is a type of synap-tic plasticity that is thought to be involved in learning and memory1. Several lines of evidence suggest that LTP involves 3′,5′-cyclic GMP (cGMP), perhaps as an activity-dependent Presynaptic effector of one or more retrograde messengers (refs 2-12, but see ref. 13). However, previous results are also consistent with postsynaptic effects of cGMP. This is difficult to test in hippocam-pal slices, but more rigorous tests are possible in dissociated cell culture14–17. We have therefore developed a reliable method for producing N-methyl-D-aspartate (NMDA) receptor-dependent LTP at synapses between individual hippocampal pyramidal Neurons in culture. We report that inhibitors of guanylyl cyclase or of cGMP-dependent protein kinase block potentiation by either tetanic stimulation or low-frequency stimulation paired with postsynaptic depolarization. Conversely, application of 8-Br-cGMP to the bath or injection of cGMP into the Presynaptic Neuron produces activity-dependent long-lasting potentiation. The potentiation by cGMP involves an increase in transmitter release that is in part independent of changes in the Presynaptic action potential. These results support a Presynaptic role for cGMP in LTP.
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tests of the roles of two diffusible substances in long term potentiation evidence for nitric oxide as a possible early retrograde messenger
Proceedings of the National Academy of Sciences of the United States of America, 1991Co-Authors: Thomas J Odell, Eric R. Kandel, Robert D Hawkins, Ottavio ArancioAbstract:Abstract Although long-term potentiation (LTP) in the CA1 region of the hippocampus is initiated postsynaptically by the influx of Ca2+ through N-methyl-D-aspartate receptor channels, the maintenance of LTP seems to be at least in part Presynaptic. This suggests that the postsynaptic cell releases a retrograde messenger to activate the Presynaptic terminals. It is likely that this messenger is membrane-permeant and reaches the Presynaptic Neuron by diffusion. We therefore have investigated two major membrane-permeant candidate retrograde messengers, arachidonic acid and nitric oxide (NO). Consistent with arachidonic acid or a lipoxygenase metabolite being a retrograde messenger, the phospholipase A2 and lipoxygenase inhibitor nordihydroguaiaretic acid blocked LTP in the guinea pig CA1 region in vitro. However, arachidonic acid (up to 100 microM) did not reliably produce activity-independent LTP, and activity-dependent potentiation by arachidonic acid was blocked by DL-aminophosphonovaleric acid. Since nordihydroguaiaretic acid also interferes with signal transduction involving NO, we next examined whether inhibitors of NO synthase block LTP. NG-Nitro-L-arginine blocked LTP when given in the bath, and this inhibition was partially overcome by high concentrations of L-arginine, suggesting that the inhibitor is specific to NO synthase. NG-Nitro-L-arginine and NG-methyl-L-arginine (but not NG-methyl-D-arginine) also blocked LTP when injected intracellularly, indicating that NO synthase is located in the postsynaptic cell. The NO, in turn, seems to be released into the extracellular space, since bathing the slice with hemoglobin, a protein that binds NO and is not taken up by cells, also blocked LTP. Moreover, NO enhances spontaneous Presynaptic release of transmitter from hippocampal Neurons in dissociated cell culture. These data favor the idea that NO might be a retrograde messenger in LTP.
David A Mccormick - One of the best experts on this subject based on the ideXlab platform.
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modulation of intracortical synaptic potentials by Presynaptic somatic membrane potential
Nature, 2006Co-Authors: Yousheng Shu, Andrea R Hasenstaub, Alvaro Duque, David A MccormickAbstract:Traditionally, Neuronal operations in the cerebral cortex have been viewed as occurring through the interaction of synaptic potentials in the dendrite and soma, followed by the initiation of an action potential, typically in the axon. Propagation of this action potential to the synaptic terminals is widely believed to be the only form of rapid communication of information between the soma and axonal synapses, and hence to postsynaptic Neurons. Here we show that the voltage fluctuations associated with dendrosomatic synaptic activity propagate significant distances along the axon, and that modest changes in the somatic membrane potential of the Presynaptic Neuron modulate the amplitude and duration of axonal action potentials and, through a Ca2+-dependent mechanism, the average amplitude of the postsynaptic potential evoked by these spikes. These results indicate that synaptic activity in the dendrite and soma controls not only the pattern of action potentials generated, but also the amplitude of the synaptic potentials that these action potentials initiate in local cortical circuits, resulting in synaptic transmission that is a mixture of triggered and graded (analogue) signals.
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modulation of intracortical synaptic potentials by Presynaptic somatic membrane potential
Nature, 2006Co-Authors: Andrea R Hasenstaub, Alvaro Duque, Yuguo Yu, David A MccormickAbstract:Rapid communication between the Neurons of the cerebral cortex involves propagation of an action potential, but the assumption that this is the sole form of cortical Neuronal communication may need revision. Whole-cell recordings point to a possible alternative mechanism. Changes in membrane potential, such as those associated with synaptic activity, can also propagate along axons and can significantly alter the average amplitude of postsynaptic potentials. This type of Neuronal signal may have important consequences, for instance in conditions such as sensory stimulation, the waking-to-sleeping transition and epileptic seizure, where large membrane potential changes occur. Traditionally, Neuronal operations in the cerebral cortex have been viewed as occurring through the interaction of synaptic potentials in the dendrite and soma, followed by the initiation of an action potential, typically in the axon1,2. Propagation of this action potential to the synaptic terminals is widely believed to be the only form of rapid communication of information between the soma and axonal synapses, and hence to postsynaptic Neurons. Here we show that the voltage fluctuations associated with dendrosomatic synaptic activity propagate significant distances along the axon, and that modest changes in the somatic membrane potential of the Presynaptic Neuron modulate the amplitude and duration of axonal action potentials and, through a Ca2+-dependent mechanism, the average amplitude of the postsynaptic potential evoked by these spikes. These results indicate that synaptic activity in the dendrite and soma controls not only the pattern of action potentials generated, but also the amplitude of the synaptic potentials that these action potentials initiate in local cortical circuits, resulting in synaptic transmission that is a mixture of triggered and graded (analogue) signals.
