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Journal articles on the topic 'Presynaptic inhibition'
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Côté, Marie-Pascale, and Jean-Pierre Gossard. "Task-Dependent Presynaptic Inhibition." Journal of Neuroscience 23, no. 5 (2003): 1886–93. http://dx.doi.org/10.1523/jneurosci.23-05-01886.2003.
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Stein, Richard B. "Presynaptic inhibition in humans." Progress in Neurobiology 47, no. 6 (1995): 533–44. http://dx.doi.org/10.1016/0301-0082(95)00036-4.
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Hayes, Heather Brant, Young-Hui Chang, and Shawn Hochman. "Stance-phase force on the opposite limb dictates swing-phase afferent presynaptic inhibition during locomotion." Journal of Neurophysiology 107, no. 11 (2012): 3168–80. http://dx.doi.org/10.1152/jn.01134.2011.
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Presynaptic inhibition is a powerful mechanism for selectively and dynamically gating sensory inputs entering the spinal cord. We investigated how hindlimb mechanics influence presynaptic inhibition during locomotion using pioneering approaches in an in vitro spinal cord–hindlimb preparation. We recorded lumbar dorsal root potentials to measure primary afferent depolarization-mediated presynaptic inhibition and compared their dependence on hindlimb endpoint forces, motor output, and joint kinematics. We found that stance-phase force on the opposite limb, particularly at toe contact, strongly influenced the magnitude and timing of afferent presynaptic inhibition in the swinging limb. Presynaptic inhibition increased in proportion to opposite limb force, as well as locomotor frequency. This form of presynaptic inhibition binds the sensorimotor states of the two limbs, adjusting sensory inflow to the swing limb based on forces generated by the stance limb. Functionally, it may serve to adjust swing-phase sensory transmission based on locomotor task, speed, and step-to-step environmental perturbations.
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AAS, P., and F. FONNUM. "Presynaptic inhibition of acetylcholine release." Acta Physiologica Scandinavica 127, no. 3 (1986): 335–42. http://dx.doi.org/10.1111/j.1748-1716.1986.tb07913.x.
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Hoffert, Marvin J. "Presynaptic inhibition of primary afferents." Journal of Pain and Symptom Management 1, no. 3 (1986): 163–64. http://dx.doi.org/10.1016/s0885-3924(86)80068-9.
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Scholz, Kenneth P. "Presynaptic inhibition in the hippocampus." Trends in Neurosciences 16, no. 10 (1993): 395–96. http://dx.doi.org/10.1016/0166-2236(93)90005-7.
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Thompson, Scott M., Marco Capogna, and Massimo Scanziani. "Presynaptic inhibition in the hippocampus." Trends in Neurosciences 16, no. 6 (1993): 222–27. http://dx.doi.org/10.1016/0166-2236(93)90160-n.
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Isaacson, Jeffry S. "GABAB Receptor-Mediated Modulation of Presynaptic Currents and Excitatory Transmission at a Fast Central Synapse." Journal of Neurophysiology 80, no. 3 (1998): 1571–76. http://dx.doi.org/10.1152/jn.1998.80.3.1571.
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Isaacson, Jeffry S. GABAB receptor-mediated modulation of presynaptic currents and excitatory transmission at a fast central synapse. J. Neurophysiol. 80: 1571–1576, 1998. Large nerve terminals (calyces of Held) in the medial nucleus of the trapezoid body (MNTB) offer a unique opportunity to explore the modulation of presynaptic channels at a mammalian central synapse. In this study I examined γ-aminobutyric acid-B (GABAB)-mediated presynaptic inhibition at the calyx of Held in slices of the rat auditory brain stem. The selective GABAB agonist baclofen caused a potent inhibition of synaptic transmission and presynaptic Ca2+ current. The inhibition of presynaptic Ca2+ channels was associated with a slowing of the activation kinetics of the underlying current, and the inhibition was relieved by strong depolarization. The inhibition of both synaptic transmission and presynaptic Ca2+ current was abolished by N-ethylmaleimide, a sulfhydryl alkylating agent that uncouples the Go/Gi class of G proteins from receptors. Baclofen does not activate a potassium conductance in the presynaptic terminal. Taken together, these results suggest that GABAB receptors inhibit synaptic transmission via G protein-mediated modulation of presynaptic Ca2+ channels at this large central synapse. Furthermore, these findings demonstrate that basic mechanisms of G protein-mediated inhibition of Ca2+ channels, proposed from recordings of neuron cell bodies, are well conserved at nerve endings in the mammalian brain.
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McComas, Alan J. "Hypothesis: Hughlings Jackson and presynaptic inhibition: is there a big picture?" Journal of Neurophysiology 116, no. 1 (2016): 41–50. http://dx.doi.org/10.1152/jn.00371.2015.
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Presynaptic inhibition is a very powerful inhibitory mechanism and, despite many detailed studies, its purpose is still only partially understood. One accepted function is that, by reducing afferent inflow to the spinal cord and brainstem, the tonic level of presynaptic inhibition prevents sensory systems from being overloaded. A corollary of this function is that much of the incoming sensory data from peripheral receptors must be redundant, and this conclusion is reinforced by observations on patients with sensory neuropathies or congenital obstetric palsy in whom normal sensation may be preserved despite loss of sensory fibers. The modulation of incoming signals by presynaptic inhibition has a further function in operating a “gate” in the dorsal horn, thereby determining whether peripheral stimuli are likely to be perceived as painful. On the motor side, the finding that even minimal voluntary movement of a single toe is associated with widespread inhibition in the lumbosacral cord points to another function for presynaptic inhibition: to prevent reflex perturbations from interfering with motor commands. This last function, together with the normal suppression of muscle and cutaneous reflex activity at rest, is consistent with Hughlings Jackson's concept of evolving neural hierarchies, with each level inhibiting the one below it.
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Frerking, M., and P. Ohliger-Frerking. "Functional Consequences of Presynaptic Inhibition During Behaviorally Relevant Activity." Journal of Neurophysiology 96, no. 4 (2006): 2139–43. http://dx.doi.org/10.1152/jn.00243.2006.
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Presynaptic inhibition is a widespread mechanism for regulating transmitter release in the CNS. Presynaptic inhibitors act as a high-pass filter, but the functional consequence of this filtering during the synaptic processing of behaviorally relevant activity remains unknown. Here we use analytical approaches to examine the effects of presynaptic inhibition on synaptic output in response to activity patterns from CA3 pyramidal cells during the performance of a complex behavioral task. We calculate that presynaptic inhibition enhances the contrast between background activity and responses to environmental cues and that neuronal responses to location are subject to stronger contrast enhancement than neuronal responses to olfactory information. Our analysis suggests that presynaptic inhibition also enhances the importance of integrative inputs that respond to many behavioral cues during the task at the expense of specific inputs that respond to only a few of these cues.
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Partovi, Dara, and Matthew Frerking. "Presynaptic inhibition by kainate receptors converges mechanistically with presynaptic inhibition by adenosine and GABAB receptors." Neuropharmacology 51, no. 6 (2006): 1030–37. http://dx.doi.org/10.1016/j.neuropharm.2006.06.010.
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Kretz, R., E. Shapiro, C. H. Bailey, M. Chen, and E. R. Kandel. "Presynaptic inhibition produced by an identified presynaptic inhibitory neuron. II. Presynaptic conductance changes caused by histamine." Journal of Neurophysiology 55, no. 1 (1986): 131–46. http://dx.doi.org/10.1152/jn.1986.55.1.131.
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We have examined the morphology and pharmacology of the L32 neurons, identified cells that mediate presynaptic inhibition in the Aplysia abdominal ganglion, to gain insight into the putative transmitter released by the L32 cells. We analyzed the fine structure of the synaptic release sites of L32 cells stained with horseradish peroxidase. Each varicosity of L32 was found to contain two general classes of vesicles. One class of vesicles is large (mean long diameter of 98 nm) and contains an electron-dense core that typically filled or nearly filled each vesicle profile. The second class of vesicles is smaller (mean long diameter of 67 nm) and relatively electron lucent. The size, distribution, and morphology of the vesicle population in L32's terminals was similar to that described at the synapses of the identified histaminergic neuron C2 in Aplysia (2). These morphological observations suggested that L32 cells might be histaminergic. Among the various putative transmitters tested, histamine was most effective in mimicking the postsynaptic effects of L32 cells onto L10, and onto other follower cells of L32 in the abdominal ganglion. Histamine also caused inhibition of transmitter output from L10. Both the IPSP produced by L32 in L10 and the response of L10 to histamine could be reversibly blocked by cimetidine, a histamine antagonist in Aplysia (14). These results support, but do not establish the identification of histamine as the putative transmitter of L32 cells. Histamine mimics the action of L32 in mediating presynaptic inhibition allowing us to examine in more detail the conductance changes in L10 underlying presynaptic inhibition. Voltage-clamp analysis revealed that histamine blocked the voltage-dependent Ca2+ current and increased a voltage-dependent K+ current in L10, much as did L32. Both of these changes are likely to act synergistically to inhibit transmitter release. Reduction of Ca2+ current in L10 would directly inhibit transmitter release from L10 directly by decreasing the amount of Ca2+ entering during spike depolarization. The increase in K+ current would act indirectly to reduce transmitter release from L10, by hyperpolarizing L10 and decreasing the amplitude and duration of spikes in L10, as well as reducing the steady-state Ca2+ influx. These results support the idea that in Aplysia presynaptic inhibition is caused primarily by a direct transmitter-mediated reduction in presynaptic Ca2+ current and secondarily by a hyperpolarization of the presynaptic neuron due to a transmitter-mediated increase in a K+ current.(ABSTRACT TRUNCATED AT 400 WORDS)
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Bogdanov, S. M., D. A. Gladchenko, L. V. Roshchina, and A. A. Chelnokov. "Effect of supraspinal influences on the manifestation of presynaptic inhibition Ia afferents in different types of muscle contraction in humans." RUDN Journal of Medicine 24, no. 4 (2020): 338–44. http://dx.doi.org/10.22363/2313-0245-2020-24-4-338-344.
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Relevance. Тhe biological role of presynaptic inhibition is to regulate excessive skeletal muscle tone, which prevents the execution of arbitrary muscle contractions. In the modern literature, there is information devoted mainly to the study of various types of spinal inhibition in the isometric type of contraction. The aim: determining the role of supraspinal influences from brain stem structures on the activity of presynaptic inhibition when performing various types and sizes of muscle contractions in humans. Materials and methods: 20-22 year-old healthy men (n=6) took part in the research. Presynaptic inhibition was registered at rest; at rest in combination with the performance of Jendrassik maneuver; when performing concentric, eccentric, isometric contractions of 50 % and 100 % of the individual maximum without and against the background of Jendrassik maneuver. Results: During the execution of concentric, eccentric and isometric contractions of different sizes, the severity of presynaptic inhibition decreases in comparison with rest, both without taking Jendrassik maneuver, and against the background of its execution. With an increase in the strength of concentric, eccentric, and isometric contractions from 50 % to 100 % of the individual maximum, the severity of presynaptic inhibition progressively decreased under the same experimental conditions. Without taking Jendrassik maneuver, the greatest severity of presynaptic inhibition was observed with concentric and isometric contractions of 50 % and 100 % of the MVC, and against the background of taking Jendrassik maneuver - with an isometric type of reduction of 50 % and 100 % of the MVC. Conclusion. Supraspinal descending effects caused by the Jendrassik maneuver modulate the state of presynaptic inhibition Ia of the afferents of the flexor muscle of the foot, depending on the type and strength of muscle contraction.
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Wu, Xin-Sheng, Jian-Yuan Sun, Alex S. Evers, Michael Crowder, and Ling-Gang Wu. "Isoflurane Inhibits Transmitter Release and the Presynaptic Action Potential." Anesthesiology 100, no. 3 (2004): 663–70. http://dx.doi.org/10.1097/00000542-200403000-00029.
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Background Isoflurane inhibits the excitatory postsynaptic current (EPSC) at many synapses. Accumulated evidence suggests the involvement of a presynaptic mechanism. However, the extent of the presynaptic contribution has not been quantitatively studied. Furthermore, the mechanism underlying the presynaptic contribution remains unclear. Methods To estimate the presynaptic contribution, the authors compared the effects of isoflurane on the presynaptic capacitance jump, which is proportional to vesicle release, and the postsynaptic glutamate receptor-mediated EPSC at a calyx-type synapse in rat brainstem. The authors determined whether isoflurane affects the waveform of the action potential recorded from nerve terminals. By studying the relation between the EPSC and the presynaptic action potential at the same synapse, the authors determined whether isoflurane inhibits the EPSC by decreasing the presynaptic action potential. Results Isoflurane at 0.35-1.05 mM reduced the EPSC and the presynaptic capacitance jump to a similar degree without affecting the miniature EPSC (an indicator of quantal size), suggesting that isoflurane inhibits the EPSC predominantly by reducing glutamate release. Isoflurane reduced the presynaptic action potential by approximately 3-8%. The EPSC was proportional to the presynaptic action potential amplitude raised to a power of 10.2. Based on this relation, inhibition of the presynaptic action potential contributed to 62-78% of isoflurane-induced inhibition of the EPSC. Conclusions Isoflurane inhibits the EPSC predominantly by inhibition of transmitter release. Isoflurane reduces the presynaptic action potential amplitude, which may contribute significantly to its inhibitory effect on the EPSC.
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Kretz, R., E. Shapiro, and E. R. Kandel. "Presynaptic inhibition produced by an identified presynaptic inhibitory neuron. I. Physiological mechanisms." Journal of Neurophysiology 55, no. 1 (1986): 113–30. http://dx.doi.org/10.1152/jn.1986.55.1.113.
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We have examined the synaptic conductance mechanisms underlying presynaptic inhibition in Aplysia californica in a circuit in which all the neural elements are identified cells (Fig. 1). L10 makes connections to identified follower cells (RB and left upper quadrant cells, L2-L6). These connections are presynaptically inhibited by stimulating cells of the L32 cluster (4). L32 cells produce a slow inhibitory synaptic potential on L10. This inhibitory synaptic potential is associated with an apparent increased membrane conductance in L10. Both the inhibitory postsynaptic potential (IPSP) and the conductance increase are voltage dependent; the IPSP could not be reversed by hyperpolarizing the membrane potentials to - 120 mV. The hyperpolarization of L10 induced by L32 reduces the transmitter output of L10 and thereby contributes to presynaptic inhibition. However, this hyperpolarization accounts for about 30% of the effect because presynaptic inhibition can still be observed even when the hyperpolarization of L10 by L32 is prevented by voltage clamping. When L10 is voltage clamped, stimulation of L32 produces a slow outward synaptic current associated with an apparent increased conductance. Both the synaptic current and conductance change measured under clamp are voltage dependent, and the outward current could not be reversed. This synaptic current is not mediated by an increase in C1- conductance. It is sensitive to external K+ concentration, especially at hyperpolarized membrane potentials. With L10 under voltage clamp, stimulation of L32 also reduces a slow inward current in L10. This current has time and voltage characteristics similar to those of the Ca2+ current. Presynaptic inhibition is still produced by L32 when L10 is voltage clamped, and transmitter release is elicited by depolarizing voltage-clamp pulses. This component of presynaptic inhibition, which accounts for approximately 70% of the inhibition, appears to be due to a decrease in the Ca2+ current in the presynaptic neuron.
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Fischer, Y., and I. Parnas. "Activation of GABAB receptors at individual release boutons of the crayfish opener neuromuscular junction produces presynaptic inhibition." Journal of Neurophysiology 75, no. 4 (1996): 1377–85. http://dx.doi.org/10.1152/jn.1996.75.4.1377.
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1. Presynaptic inhibition in crustaceans involves the activation of gamma-aminobutyric acid-A (GABAA) receptors that produce an increase in chloride conductance at excitatory axon terminals. Such inhibition produced by single inhibitory pulses is blocked by picrotoxin, a GABAA antagonist. 2. Presynaptic inhibition produced by bath application of GABA was not blocked by picrotoxin. Measurements of the membrane resistance of the excitatory axon terminals revealed that substantial presynaptic inhibition still persisted after 50 microM picrotoxin had completely blocked the increase in conductance produced by 10 microM GABA. 3. Baclofen, a GABAB agonist, reduced release from the excitatory nerve terminals, and 20H-Saclofen, a GABAB antagonist, blocked the effect of baclofen and the presynaptic inhibition produced by 10 microM GABA. 4. 20H-Saclofen alone did not block presynaptic inhibition produced by 100 microM GABA, and the combined action of both 20H-Saclofen and picrotoxin was required to block such effects. 5. The excitatory nerve terminals seem to contain GABAA and GABAB receptors. The GABAB receptors are preferentially activated at lower GABA concentrations (in the microM range), whereas both the GABAA and GABAB receptors are activated at high GABA concentrations.
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Enríquez-Denton, M., H. Morita, L. O. D. Christensen, N. Petersen, T. Sinkjaer, and J. B. Nielsen. "Interaction Between Peripheral Afferent Activity and Presynaptic Inhibition of Ia Afferents in the Cat." Journal of Neurophysiology 88, no. 4 (2002): 1664–74. http://dx.doi.org/10.1152/jn.2002.88.4.1664.
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It has been demonstrated in man that the H-reflex is more depressed by presynaptic inhibition than the stretch reflex. Here we investigated this finding further in the alpha-chloralose-anesthetized cat. Soleus monosynaptic reflexes were evoked by electrical stimulation of the tibial nerve or by stretch of the triceps surae muscle. Conditioning stimulation of the posterior biceps and semitendinosus nerve (PBSt) produced a significantly stronger depression of the electrically than the mechanically evoked reflexes. The depression of the reflexes has been shown to be caused by presynaptic inhibition of triceps surae Ia afferents. We investigated the hypothesis that repetitive activation of peripheral afferents may reduce their sensitivity to presynaptic inhibition. In triceps surae motoneurones, we measured the effect of presynaptic inhibition on excitatory postsynaptic potentials (EPSPs) produced by repetitive activation of the peripheral afferents or by fast and slow muscle stretch. EPSPs evoked by single electrical stimulation of the tibial nerve or by fast muscle stretch were significantly depressed by PBSt stimulation. However, the last EPSP in a series of EPSPs evoked by a train of electrical stimuli (5–6 shocks, 150–200 Hz) was significantly less depressed by the conditioning stimulation than the first EPSP. In addition, the last part of the long-lasting EPSPs evoked by a slow muscle stretch was also less depressed than the first part. A single EPSP evoked by stimulation of the medial gastrocnemius nerve was less depressed when preceded by a train of stimuli applied to the same nerve than when the same train of stimuli was applied to a synergistic nerve. The decreased sensitivity of the test EPSP to presynaptic inhibition was maximal when it was evoked within 20 ms after the train of EPSPs. It was not observed at intervals longer than 30 ms. These findings suggest that afferent activity may decrease the efficiency of presynaptic inhibition. We propose that the described interaction between afferent nerve activity and presynaptic inhibition may partly explain why electrically and mechanically evoked reflexes are differently sensitive to presynaptic inhibition.
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Yamauchi, Tatsuhito, Tetsuya Hori, and Tomoyuki Takahashi. "Presynaptic inhibition by muscimol through GABABreceptors." European Journal of Neuroscience 12, no. 9 (2000): 3433–36. http://dx.doi.org/10.1046/j.1460-9568.2000.00248.x.
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Guo, D., and J. Hu. "Spinal presynaptic inhibition in pain control." Neuroscience 283 (December 2014): 95–106. http://dx.doi.org/10.1016/j.neuroscience.2014.09.032.
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Wu, Ling-Gang, and Peter Saggau. "Presynaptic inhibition of elicited neurotransmitter release." Trends in Neurosciences 20, no. 5 (1997): 204–12. http://dx.doi.org/10.1016/s0166-2236(96)01015-6.
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Rudomin, Pablo. "In search of lost presynaptic inhibition." Experimental Brain Research 196, no. 1 (2009): 139–51. http://dx.doi.org/10.1007/s00221-009-1758-9.
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Segal, Menahem. "Presynaptic cholinergic inhibition in hippocampal cultures." Synapse 4, no. 4 (1989): 305–12. http://dx.doi.org/10.1002/syn.890040406.
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Glantz, Raymon M., Lolin Wang-Bennett, and Brian Waldrop. "Presynaptic inhibition in the crayfish brain." Journal of Comparative Physiology A 156, no. 4 (1985): 477–87. http://dx.doi.org/10.1007/bf00613972.
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Wang-Bennett, Lolin T., and Raymon M. Glantz. "Presynaptic inhibition in the crayfish brain." Journal of Comparative Physiology A 156, no. 5 (1985): 605–17. http://dx.doi.org/10.1007/bf00619110.
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Tse, FW, and HL Atwood. "Presynaptic Inhibition at the Crustacean Neuromuscular Junction." Physiology 1, no. 2 (1986): 47–50. http://dx.doi.org/10.1152/physiologyonline.1986.1.2.47.
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Many crustacean muscles are innervated by only one or a few excitatory axons that make the whole muscle act much as a single unit. Modulation of contraction and a graded response is achieved through inhibitory impulses, mostly at the presynaptic level. Crustacean muscle is therefore remarkably well suited for studies of presynaptic inhibition.
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Fischer, Y., and I. Parnas. "Differential activation of two distinct mechanisms for presynaptic inhibition by a single inhibitory axon." Journal of Neurophysiology 76, no. 6 (1996): 3807–16. http://dx.doi.org/10.1152/jn.1996.76.6.3807.
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1. Presynaptic inhibition of excitatory transmitter release evoked by inhibitory axon stimulation was studied at individual release boutons of the crayfish opener neuromuscular junction. 2. Presynaptic inhibition was maximal (approximately 30%) when a single inhibitory action potential preceded the excitatory test action potential by 1–2 ms. This inhibition lasted at most 5 ms. It was blocked by 50 microM picrotoxin, and is probably mediated mainly by gamma-aminobutyric acid-A (GABAA) receptors. 3. Presynaptic inhibition produced by a brief train of inhibitory action potentials (5 pulses at 100 Hz) was maximal (approximately 60%) when the last inhibitory action potential (of the train) preceded the excitatory test action potential by 10 ms. This inhibition lasted up to 50 ms. It seems that in this case GABAB receptors were activated as well, because the combined action of picrotoxin (50 microM) and 20H-Saclofen (100 microM) was required to block the inhibition. 4. We thus show that one and the same inhibitory release bouton can differentially activate two distinct mechanisms for presynaptic inhibition by activating GABAA and GABAB receptors.
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Parnas, I., G. Rashkovan, R. Ravin, and Y. Fischer. "Novel Mechanism for Presynaptic Inhibition: GABAAReceptors Affect the Release Machinery." Journal of Neurophysiology 84, no. 3 (2000): 1240–46. http://dx.doi.org/10.1152/jn.2000.84.3.1240.
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Presynaptic inhibition is produced by increasing Cl− conductance, resulting in an action potential of a smaller amplitude at the excitatory axon terminals. This, in turn, reduces Ca2+ entry to produce a smaller release. For this mechanism to operate, the “inhibitory” effect of shunting should last during the arrival of the “excitatory” action potential to its terminals, and to achieve that, the inhibitory action potential should precede the excitatory action potential. Using the crayfish neuromuscular preparation which is innervated by one excitatory axon and one inhibitory axon, we found, at 12°C, prominent presynaptic inhibition when the inhibitory action potential followed the excitatory action potential by 1, and even 2, ms. The presynaptic excitatory action potential and the excitatory nerve terminal current (ENTC) were not altered, and Ca2+imaging at single release boutons showed that this “late” presynaptic inhibition did not result from a reduction in Ca2+ entry. Since 50 μM picrotoxin blocked this late component of presynaptic inhibition, we suggest that γ-aminobutyric acid-A (GABAA) receptors reduce transmitter release also by a mechanism other than affecting Ca2+ entry.
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Knikou, Maria, and Chaithanya K. Mummidisetty. "Locomotor training improves premotoneuronal control after chronic spinal cord injury." Journal of Neurophysiology 111, no. 11 (2014): 2264–75. http://dx.doi.org/10.1152/jn.00871.2013.
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Spinal inhibition is significantly reduced after spinal cord injury (SCI) in humans. In this work, we examined if locomotor training can improve spinal inhibition exerted at a presynaptic level. Sixteen people with chronic SCI received an average of 45 training sessions, 5 days/wk, 1 h/day. The soleus H-reflex depression in response to low-frequency stimulation, presynaptic inhibition of soleus Ia afferent terminals following stimulation of the common peroneal nerve, and bilateral EMG recovery patterns were assessed before and after locomotor training. The soleus H reflexes evoked at 1.0, 0.33, 0.20, 0.14, and 0.11 Hz were normalized to the H reflex evoked at 0.09 Hz. Conditioned H reflexes were normalized to the associated unconditioned H reflex evoked with subjects seated, while during stepping both H reflexes were normalized to the maximal M wave evoked after the test H reflex at each bin of the step cycle. Locomotor training potentiated homosynaptic depression in all participants regardless the type of the SCI. Presynaptic facilitation of soleus Ia afferents remained unaltered in motor complete SCI patients. In motor incomplete SCIs, locomotor training either reduced presynaptic facilitation or replaced presynaptic facilitation with presynaptic inhibition at rest. During stepping, presynaptic inhibition was modulated in a phase-dependent manner. Locomotor training changed the amplitude of locomotor EMG excitability, promoted intralimb and interlimb coordination, and altered cocontraction between knee and ankle antagonistic muscles differently in the more impaired leg compared with the less impaired leg. The results provide strong evidence that locomotor training improves premotoneuronal control after SCI in humans at rest and during walking.
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Lamy, Jean-Charles, Heike Russmann, Ejaz A. Shamim, Sabine Meunier, and Mark Hallett. "Paired Associative Stimulation Induces Change in Presynaptic Inhibition of Ia Terminals in Wrist Flexors in Humans." Journal of Neurophysiology 104, no. 2 (2010): 755–64. http://dx.doi.org/10.1152/jn.00761.2009.
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Enhancements in the strength of corticospinal projections to muscles are induced in conscious humans by paired associative stimulation (PAS) to the motor cortex. Although most of the previous studies support the hypothesis that the increase of the amplitude of motor evoked potentials (MEPs) by PAS involves long-term potentiation (LTP)-like mechanism in cortical synapses, changes in spinal excitability after PAS have been reported, suggestive of parallel modifications in both cortical and spinal excitability. In a first series of experiments ( experiment 1), we confirmed that both flexor carpi radialis (FCR) MEPs and FCR H reflex recruitment curves are enhanced by PAS. To elucidate the mechanism responsible for this change in the H reflex amplitude, we tested, using the same subjects, the hypothesis that enhanced H reflexes are caused by a down-regulation of the efficacy of mechanisms controlling Ia afferent discharge, including presynaptic Ia inhibition and postactivation depression. To address this question, amounts of both presynaptic Ia inhibition of FCR Ia terminals (D1and D2 inhibitions methods; experiment 2) and postactivation depression ( experiment 3) were determined before and after PAS. Results showed that PAS induces a significant decrease of presynaptic Ia inhibition of FCR terminals, which was concomitant with the facilitation of the H reflex. Postactivation depression was unaffected by PAS. It is argued that enhancement of segmental excitation by PAS relies on a selective effect of PAS on the interneurons controlling presynaptic inhibition of Ia terminals.
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Scholz, K. P., and R. J. Miller. "Presynaptic inhibition at excitatory hippocampal synapses: development and role of presynaptic Ca2+ channels." Journal of Neurophysiology 76, no. 1 (1996): 39–46. http://dx.doi.org/10.1152/jn.1996.76.1.39.
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1. Presynaptic inhibition of excitatory postsynaptic currents (EPSCs) induced by activation of adenosine receptors was examined at hippocampal synapses in cell culture. Changes in the degree of presynaptic inhibition during development were examined. The results were then used to test the role of presynaptic Ca2+ channels in presynaptic inhibition. 2. Application of the selective A1 adenosine receptor agonist N6-cyclopentyladenosine (CPA) reduced EPSCs measured with the use of whole cell voltage-clamp procedures. In cells grown in culture for < 15 days, CPA (100 nM) inhibited EPSCs by 74 +/- 2%. In cells grown in culture for > 20 days, the same concentration of CPA inhibited EPSCs by 47 +/- 3%. 3. In mature cells (grown in culture for > 20 days), application of the selective N-type Ca2+ channel blocker omega-conotoxin GVIA (omega-CTx GVIA; 2.5 microM) partially occluded the effects of CPA. In contrast, the P/Q channel blocker omega-Aga IVA enhanced the effects of CPA. Both toxins reduced the amplitude of the EPSC. 4. omega-CTx GVIA was applied to the EPSC that remained after application of 100 nM CPA. Under these conditions, omega-CTx GVIA reduced the EPSC by less than when omega-CTx GVIA was applied under control conditions. In contrast, when omega-Aga IVA was applied in the presence of CPA, the toxin reduced the EPSC to a greater extent than when it was applied under control conditions. 5. Somatic Ca(2+)-channel currents were inhibited by CPA. This effect was partially occluded by pretreatment with omega-CTx GVIA but was unaffected by pretreatment with omega-Aga IVA (1 microM). Both toxins blocked part of the somatic Ca(2+)-channel current. 6. The results indicate that inhibition of presynaptic N-type Ca2+ channels accounted for 40-50% of presynaptic inhibition, another type of Ca2+ channel may participate as well. In addition, the efficacy of presynaptic inhibition declined during synapse maturation due in part to a developmental decline in the relative contribution of N-type channels to transmitter release.
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Stein, Wolfgang, and Josef Schmitz. "Multimodal Convergence of Presynaptic Afferent Inhibition in Insect Proprioceptors." Journal of Neurophysiology 82, no. 1 (1999): 512–14. http://dx.doi.org/10.1152/jn.1999.82.1.512.
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In the leg motor system of insects, several proprioceptive sense organs provide the CNS with information about posture and movement. Within one sensory organ, presynaptic inhibition shapes the inflow of sensory information to the CNS. We show here that also different proprioceptive sense organs can exert a presynaptic inhibition on each other. The afferents of one leg proprioceptor in the stick insect, either the position-sensitive femoral chordotonal organ or the load-sensitive campaniform sensilla, receive a primary afferent depolarization (PAD) from two other leg proprioceptors, the campaniform sensilla and/or the coxal hairplate. The reversal potential of this PAD is about −59 mV, and the PAD is associated with a conductance increase. The properties of this presynaptic input support the hypothesis that this PAD acts as presynaptic inhibition. The PAD reduces the amplitude of afferent action potentials and thus likely also afferent transmitter release and synaptic efficacy. These findings imply that PAD mechanisms of arthropod proprioceptors might be as complex as in vertebrates.
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Blundon, J. A., and G. D. Bittner. "Effects of ethanol and other drugs on excitatory and inhibitory neurotransmission in the crayfish." Journal of Neurophysiology 67, no. 3 (1992): 576–87. http://dx.doi.org/10.1152/jn.1992.67.3.576.
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1. Crayfish exposed to 434 mM ethanol (EtOH) showed signs of hyperactivity within 0.5-2 h, at which times crayfish hemolymph EtOH concentration had reached 60-90 mM. 2. A 10-min exposure to 60-90 mM EtOH reduced presynaptic inhibition of excitatory postsynaptic currents (EPSCs) at the crayfish opener neuromuscular junction (NMJ) in vitro but did not significantly alter excitatory neurotransmission. The same concentrations of EtOH did not alter other potentials or currents associated with inhibition at this synapse, such as presynaptic inhibitory potentials (PIPs), inhibitory postsynaptic potentials (IPSPs), and inhibitory postsynaptic currents (IPSCs). 3. Intermediate EtOH concentrations (120-180 mM) applied for 10 min in vitro reduced the amplitude of excitatory postsynaptic potentials (EPSPs) by decreasing the membrane resistance of opener muscle fibers and by reducing the amplitude of EPSCs. 4. High EtOH concentrations (434 mM) applied for 10 min in vitro had yet greater depressive effects on measures of postsynaptic properties described above. The time course of EPSCs was also significantly reduced. In addition, presynaptic properties such as action-potential (AP) amplitude and frequency of spontaneous release of neurotransmitter were reduced by 434 mM EtOH. 5. Presynaptic inhibition, gamma-aminobutyric acid (GABA; 250-500 microM), muscimol (50 microM), and baclofen (75 microM) all reduced the depolarizing afterpotential of APs in the excitor axon and reduced EPSPs in opener muscle fibers. GABA (500 microM) and baclofen (75 microM) significantly reduced presynaptic AP amplitudes, whereas presynaptic inhibition, GABA (250 microM), and muscimol (50 microM) had no effect on AP amplitude. Bicuculline (250-500 microM), a GABAA antagonist, did not entirely eliminate presynaptic inhibition, whereas picrotoxin (50 microM), another GABAA antagonist, completely removed presynaptic inhibition. Thus presynaptic inhibitory mechanisms may involve both GABAA and GABAB receptors on the opener excitor axon. 6. Our data suggest that the behavioral hyperactivity seen at hemolymph EtOH concentrations of 60-90 mM is not accompanied by a change in excitatory synaptic transmission observed at the opener NMJ. Rather, crayfish hyperactivity may be due to depressive effects of EtOH on inhibitory synapses in the CNS similar to the disinhibition evoked by EtOH at the opener NMJ.
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BLAGBURN, JONATHAN M., and DAVID B. SATTELLE. "Presynaptic Depolarization Mediates Presynaptic Inhibition at a Synapse Between An Identified Mechanosensory Neurone and Giant Interneurone 3 in the First Instar Cockroach, Periplaneta Americana." Journal of Experimental Biology 127, no. 1 (1987): 135–57. http://dx.doi.org/10.1242/jeb.127.1.135.
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Intracellular microelectrodes were used to study presynaptic inhibition at a cholinergic synapse between identified neurones: the lateral filiform hair sensory neurone (LFHSN) and giant interneurone 3 (GI3) in the terminal ganglion of the first instar cockroach Periplaneta americana. The LFHSN-GI3 synapse was shown to fulfil physiological criteria for monosynaptic transmission: the latency of the EPSPs was 1.4 ms and was constant during high-frequency firing of LFHSN; transmission was progressively and reversibly abolished by replacement of Ca2+ with Mg2+. Movement of the lateral filiform hair towards the cereal tip produced a burst of spikes in LFHSN and a burst of EPSPs in GI 3. Movement of the medial filiform hair towards the base of the cercus produced a burst of spikes in the medial filiform hair sensory neurone (MFHSN) and a burst of EPSPs in GI 2. EPSPs evoked in GI 3 by LFHSN spikes were inhibited during bursts of EPSPs in GI 2 which were evoked by MFHSN spikes. LFHSN was depolarized and its spikes were reduced in amplitude during spike bursts in MFHSN. Reduction in LFHSN spike amplitude reduced GI 3 EPSPs. This phenomenon was attributed, therefore, to presynaptic inhibition. The occurrence of presynaptic inhibition was dependent upon the degree of delayed rectification exhibited by the LFHSN axon. Hyperpolarization of LFHSN increased spike height, but did not increase the amplitude of GI 3 EPSPs. The delay between the onset of MFHSN-evoked EPSPs in GI 2 and MFHSNevoked depolarizations in LFHSN suggested that MFHSN does not synapse directly onto LFHSN. Neither depolarization nor hyperpolarization of GI 2 had any effect on MFHSN-mediated presynaptic inhibition of LFHSN-GI 3 transmission, therefore it was considered unlikely that GI 2 synapses onto LFHSN. Prolonged hyperpolarization lowered the LFHSN spike threshold and temporarily abolished presynaptic inhibition. Bursts of spikes in LFHSN mediated presynaptic inhibition of MFHSN-GI2 EPSPs. Mutual presynaptic inhibition by the FHSNs may have a functional significance in sharpening the boundaries of the GIs' directional sensitivities.
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Pinto, Maria J., Pedro L. Alves, Luís Martins, et al. "The proteasome controls presynaptic differentiation through modulation of an on-site pool of polyubiquitinated conjugates." Journal of Cell Biology 212, no. 7 (2016): 789–801. http://dx.doi.org/10.1083/jcb.201509039.
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Differentiation of the presynaptic terminal is a complex and rapid event that normally occurs in spatially specific axonal regions distant from the soma; thus, it is believed to be dependent on intra-axonal mechanisms. However, the full nature of the local events governing presynaptic assembly remains unknown. Herein, we investigated the involvement of the ubiquitin–proteasome system (UPS), the major degradative pathway, in the local modulation of presynaptic differentiation. We found that proteasome inhibition has a synaptogenic effect on isolated axons. In addition, formation of a stable cluster of synaptic vesicles onto a postsynaptic partner occurs in parallel to an on-site decrease in proteasome degradation. Accumulation of ubiquitinated proteins at nascent sites is a local trigger for presynaptic clustering. Finally, proteasome-related ubiquitin chains (K11 and K48) function as signals for the assembly of presynaptic terminals. Collectively, we propose a new axon-intrinsic mechanism for presynaptic assembly through local UPS inhibition. Subsequent on-site accumulation of proteins in their polyubiquitinated state triggers formation of presynapses.
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Sandstrom, David J. "Isoflurane Reduces Excitability of Drosophila Larval Motoneurons by Activating a Hyperpolarizing Leak Conductance." Anesthesiology 108, no. 3 (2008): 434–46. http://dx.doi.org/10.1097/aln.0b013e318164cfda.
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Background Mechanisms of anesthetic-mediated presynaptic inhibition are incompletely understood. Isoflurane reduces presynaptic excitability at the larval Drosophila neuromuscular junction, slowing conduction velocity and depressing glutamate release. Mutations in the Para voltage-gated Na channel enhance anesthetic sensitivity of adult flies. Here, the author examines the role of para in anesthetic sensitivity and seeks to identify the conductance underlying presynaptic inhibition at this synapse. Methods Neuromuscular transmission was studied using a two-electrode voltage clamp, with isoflurane applied in physiologic saline. The relation between ionic conductances and presynaptic function was modeled in the Neuron Simulation Environment. Motoneuron ionic currents were monitored via whole cell recordings. Results Presynaptic inhibition by isoflurane was enhanced significantly in para mutants. Computer simulations of presynaptic actions of anesthetics indicated that each candidate target conductance would have diagnostic effects on the relation between latency and amplitude of synaptic currents. The experimental latency-amplitude relation for isoflurane most closely resembled activation of a simulated hyperpolarizing leak. Simulations indicated that increased isoflurane potency in para axons resulted from reduced excitability of mutant axons. In whole cell recordings, isoflurane activated a hyperpolarizing leak current. The effects of isoflurane at the neuromuscular junction were insensitive to low pH. Conclusions The effects of isoflurane on presynaptic excitability are mediated via an acid-insensitive inhibitory leak conductance. para mutations enhance the sensitivity of this anesthetic-modulated neural pathway by reducing axonal excitability. This work provides a link between anesthetic-sensitive leak currents and presynaptic function and has generated new tools for analysis of the function of this synapse.
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Oshima-Takago, Tomoko, and Hideki Takago. "NMDA receptor-dependent presynaptic inhibition at the calyx of Held synapse of rat pups." Open Biology 7, no. 7 (2017): 170032. http://dx.doi.org/10.1098/rsob.170032.
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N -Methyl- d -aspartate receptors (NMDARs) play diverse roles in synaptic transmission, synaptic plasticity, neuronal development and neurological diseases. In addition to their postsynaptic expression, NMDARs are also expressed in presynaptic terminals at some central synapses, and their activation modulates transmitter release. However, the regulatory mechanisms of NMDAR-dependent synaptic transmission remain largely unknown. In the present study, we demonstrated that activation of NMDARs in a nerve terminal at a central glutamatergic synapse inhibits presynaptic Ca 2+ currents (I Ca ) in a GluN2C/2D subunit-dependent manner, thereby decreasing nerve-evoked excitatory postsynaptic currents. Neither presynaptically loaded fast Ca 2+ chelator BAPTA nor non-hydrolysable GTP analogue GTPγS affected NMDAR-mediated I Ca inhibition. In the presence of a glutamate uptake blocker, the decline in I Ca amplitude evoked by repetitive depolarizing pulses at 20 Hz was attenuated by an NMDAR competitive antagonist, suggesting that endogenous glutamate has a potential to activate presynaptic NMDARs. Moreover, NMDA-induced inward currents at a negative holding potential (−80 mV) were abolished by intra-terminal loading of the NMDAR open channel blocker MK-801, indicating functional expression of presynaptic NMDARs. We conclude that presynaptic NMDARs can attenuate glutamate release by inhibiting voltage-gated Ca 2+ channels at a relay synapse in the immature rat auditory brainstem.
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Hoffman, M. A., J. R. Doeringer, M. F. Norcross, S. T. Johnson, and P. E. Chappell. "Presynaptic inhibition decreases when estrogen level rises." Scandinavian Journal of Medicine & Science in Sports 28, no. 9 (2018): 2009–15. http://dx.doi.org/10.1111/sms.13210.
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Cervero, Fernando, Jennifer M. A. Laird, and Esther García-Nicas. "Secondary hyperalgesia and presynaptic inhibition: an update." European Journal of Pain 7, no. 4 (2003): 345–51. http://dx.doi.org/10.1016/s1090-3801(03)00047-8.
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Nusbaum, Michael P., and Diego Contreras. "Sensorimotor Gating: Startle Submits to Presynaptic Inhibition." Current Biology 14, no. 6 (2004): R247—R249. http://dx.doi.org/10.1016/j.cub.2004.02.059.
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Swash, Michael, and Mamede de Carvalho. "Measuring spinal presynaptic inhibition in human subjects." Clinical Neurophysiology 131, no. 8 (2020): 1966–67. http://dx.doi.org/10.1016/j.clinph.2020.04.015.
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Shen, W. X., and J. P. Horn. "Presynaptic muscarinic inhibition in bullfrog sympathetic ganglia." Journal of Physiology 491, no. 2 (1996): 413–21. http://dx.doi.org/10.1113/jphysiol.1996.sp021225.
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Ratnakumari, Lingamaneni, and Hugh C. Hemmings. "Inhibition of Presynaptic Sodium Channels by Halothane." Anesthesiology 88, no. 4 (1998): 1043–54. http://dx.doi.org/10.1097/00000542-199804000-00025.
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Background Recent electrophysiologic studies indicate that clinical concentrations of volatile general anesthetic agents inhibit central nervous system sodium (Na+) channels. In this study, the biochemical effects of halothane on Na+ channel function were determined using rat brain synaptosomes (pinched-off nerve terminals) to assess the role of presynaptic Na+ channels in anesthetic effects. Methods Synaptosomes from adult rat cerebral cortex were used to determine the effects of halothane on veratridine-evoked Na+ channel-dependent Na+ influx (using 22Na+), changes in intrasynaptosomal [Na+] (using ion-specific spectrofluorometry), and neurotoxin interactions with specific receptor sites of the Na+ channel (by radioligand binding). The potential physiologic and functional significance of these effects was determined by measuring the effects of halothane on veratridine-evoked Na+ channel-dependent glutamate release (using enzyme-coupled spectrofluorometry). Results Halothane inhibited veratridine-evoked 22Na+ influx (IC50 = 1.1 mM) and changes in intrasynaptosomal [Na+] (concentration for 50% inhibition [IC50] = 0.97 mM), and it specifically antagonized [3H]batrachotoxinin-A 20-alpha-benzoate binding to receptor site two of the Na+ channel (IC50 = 0.53 mM). Scatchard and kinetic analysis revealed an allosteric competitive mechanism for inhibition of toxin binding. Halothane inhibited veratridine-evoked glutamate release from synaptosomes with comparable potency (IC50 = 0.67 mM). Conclusions Halothane significantly inhibited Na+ channel-mediated Na influx, increases in intrasynaptosomal [Na+] and glutamate release, and competed with neurotoxin binding to site two of the Na+ channel in synaptosomes at concentrations within its clinical range (minimum alveolar concentration, 1-2). These findings support a role for presynaptic Na+ channels as a molecular target for general anesthetic effects.
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Hurwitz, Itay, Abraham J. Susswein, and Klaudiusz R. Weiss. "Transforming Tonic Firing Into a Rhythmic Output in the Aplysia Feeding System: Presynaptic Inhibition of a Command-Like Neuron by a CPG Element." Journal of Neurophysiology 93, no. 2 (2005): 829–42. http://dx.doi.org/10.1152/jn.00559.2004.
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Tonic stimuli can elicit rhythmic responses. The neural circuit underlying Aplysia californica consummatory feeding was used to examine how a maintained stimulus elicits repetitive, rhythmic movements. The command-like cerebral-buccal interneuron 2 (CBI-2) is excited by tonic food stimuli but initiates rhythmic consummatory responses by exciting only protraction-phase neurons, which then excite retraction-phase neurons after a delay. CBI-2 is inhibited during retraction, generally preventing it from exciting protraction-phase neurons during retraction. We have found that depolarizing CBI-2 during retraction overcomes the inhibition and causes CBI-2 to fire, potentially leading CBI-2 to excite protraction-phase neurons during retraction. However, CBI-2 synaptic outputs to protraction-phase neurons were blocked during retraction, thereby preventing excitation during retraction. The block was caused by presynaptic inhibition of CBI-2 by a key buccal ganglion retraction-phase interneuron, B64, which also causes postsynaptic inhibition of protraction-phase neurons. Pre- and postsynaptic inhibition could be separated. First, only presynaptic inhibition affected facilitation of excitatory postsynaptic potentials (EPSPs) from CBI-2 to its followers. Second, a newly identified neuron, B54, produced postsynaptic inhibition similar to that of B64 but did not cause presynaptic inhibition. Third, in some target neurons B64 produced only presynaptic but not postsynaptic inhibition. Blocking CBI-2 transmitter release in the buccal ganglia during retraction functions to prevent CBI-2 from driving protraction-phase neurons during retraction and regulates the facilitation of the CBI-2 induced EPSPs in protraction-phase neurons.
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Porter, James T., and Dalila Nieves. "Presynaptic GABAB Receptors Modulate Thalamic Excitation of Inhibitory and Excitatory Neurons in the Mouse Barrel Cortex." Journal of Neurophysiology 92, no. 5 (2004): 2762–70. http://dx.doi.org/10.1152/jn.00196.2004.
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Cortical inhibition plays an important role in the processing of sensory information, and the enlargement of receptive fields by the in vivo application of GABAB receptor antagonists indicates that GABAB receptors mediate some of this cortical inhibition. Although there is evidence of postsynaptic GABAB receptors on cortical neurons, there is no evidence of GABAB receptors on thalamocortical terminals. Therefore to determine if presynaptic GABAB receptors modulate the thalamic excitation of layer IV inhibitory neurons and excitatory neurons in layers II–III and IV of the somatosensory “barrel” cortex of mice, we used a thalamocortical slice preparation and patch-clamp electrophysiology. Stimulation of the ventrobasal thalamus elicited excitatory postsynaptic currents (EPSCs) in cortical neurons. Bath application of baclofen, a selective GABAB receptor agonist, reversibly decreased AMPA receptor-mediated and N-methyl-d-aspartate (NMDA) receptor-mediated EPSCs in inhibitory and excitatory neurons. The GABAB receptor antagonist, CGP 35348, reversed the inhibition produced by baclofen. Blocking the postsynaptic GABAB receptor-mediated effects with a Cs+-based recording solution did not affect the inhibition, suggesting a presynaptic effect of baclofen. Baclofen reversibly increased the paired-pulse ratio and the coefficient of variation, consistent with the presynaptic inhibition of glutamate release. Our results indicate that the presynaptic activation of GABAB receptors modulates thalamocortical excitation of inhibitory and excitatory neurons and provide another mechanism by which cortical inhibition can modulate the processing of sensory information.
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Zurawski, Zack, Yun Young Yim, Simon Alford, and Heidi E. Hamm. "The expanding roles and mechanisms of G protein–mediated presynaptic inhibition." Journal of Biological Chemistry 294, no. 5 (2019): 1661–70. http://dx.doi.org/10.1074/jbc.tm118.004163.
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Throughout the past five decades, tremendous advancements have been made in our understanding of G protein signaling and presynaptic inhibition, many of which were published in the Journal of Biological Chemistry under the tenure of Herb Tabor as Editor-in-Chief. Here, we identify these critical advances, including the formulation of the ternary complex model of G protein–coupled receptor signaling and the discovery of Gβγ as a critical signaling component of the heterotrimeric G protein, along with the nature of presynaptic inhibition and its physiological role. We provide an overview for the discovery and physiological relevance of the two known Gβγ–mediated mechanisms for presynaptic inhibition: first, the action of Gβγ on voltage-gated calcium channels to inhibit calcium influx to the presynaptic active zone and, second, the direct binding of Gβγ to the SNARE complex to displace synaptotagmin downstream of calcium entry, which has been demonstrated to be important in neurons and secretory cells. These two mechanisms act in tandem with each other in a synergistic manner to provide more complete spatiotemporal control over neurotransmitter release.
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Alexander, Georgia M., and Dwayne W. Godwin. "Presynaptic Inhibition of Corticothalamic Feedback by Metabotropic Glutamate Receptors." Journal of Neurophysiology 94, no. 1 (2005): 163–75. http://dx.doi.org/10.1152/jn.01198.2004.
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The thalamus relays sensory information to cortex, but this information may be influenced by excitatory feedback from cortical layer VI. The full importance of this feedback has only recently been explored, but among its possible functions are influences on the processing of sensory features, synchronization of thalamic firing, and transitions in response mode of thalamic relay cells. Uncontrolled, corticothalamic feedback has also been implicated in pathological thalamic rhythms associated with certain neurological disorders. We have found a form of presynaptic inhibition of corticothalamic synaptic transmission that is mediated by a Group II metabotropic glutamate receptor (mGluR) and activated by high-frequency corticothalamic activity. We tested putative retinogeniculate and corticogeniculate synapses for Group II mGluR modulation within the dorsal lateral geniculate nucleus of the ferret thalamus. Stimulation of optic-tract fibers elicited paired-pulse depression of excitatory postsynaptic currents (EPSCs), whereas stimulation of the optic radiations elicited paired-pulse facilitation. Paired-pulse responses were subsequently used to characterize the pathway of origin of stimulated synapses. Group II mGluR agonists (LY379268 and DCG-IV) applied to thalamic neurons under voltage-clamp conditions reduced the amplitude of corticogeniculate EPSCs. Stimulation with high-frequency trains produced a facilitating response that was reduced by Group II mGluR agonists, but was enhanced by the selective antagonist LY341495, revealing a presynaptic, mGluR-mediated reduction of high-frequency corticogeniculate feedback. Agonist treatment did not affect EPSCs from stimulation of the optic tract. NAAG (reported to be selective for mGluR3) was ineffective at the corticogeniculate synapse, implicating mGluR2 in the observed effects. Our data are the first to show a synaptically elicited form of presynaptic inhibition of corticothalamic synaptic transmission that is mediated by presynaptic action of mGluR2. This presynaptic inhibition may partially mute sensory feedback and prevent reentrant excitation from initiating abnormal thalamic rhythms.
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Lujan, Brendan, Christopher Kushmerick, Tania Das Banerjee, Ruben K. Dagda, and Robert Renden. "Glycolysis selectively shapes the presynaptic action potential waveform." Journal of Neurophysiology 116, no. 6 (2016): 2523–40. http://dx.doi.org/10.1152/jn.00629.2016.
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Mitochondria are major suppliers of cellular energy in neurons; however, utilization of energy from glycolysis vs. mitochondrial oxidative phosphorylation (OxPhos) in the presynaptic compartment during neurotransmission is largely unknown. Using presynaptic and postsynaptic recordings from the mouse calyx of Held, we examined the effect of acute selective pharmacological inhibition of glycolysis or mitochondrial OxPhos on multiple mechanisms regulating presynaptic function. Inhibition of glycolysis via glucose depletion and iodoacetic acid (1 mM) treatment, but not mitochondrial OxPhos, rapidly altered transmission, resulting in highly variable, oscillating responses. At reduced temperature, this same treatment attenuated synaptic transmission because of a smaller and broader presynaptic action potential (AP) waveform. We show via experimental manipulation and ion channel modeling that the altered AP waveform results in smaller Ca2+ influx, resulting in attenuated excitatory postsynaptic currents (EPSCs). In contrast, inhibition of mitochondria-derived ATP production via extracellular pyruvate depletion and bath-applied oligomycin (1 μM) had no significant effect on Ca2+ influx and did not alter the AP waveform within the same time frame (up to 30 min), and the resultant EPSC remained unaffected. Glycolysis, but not mitochondrial OxPhos, is thus required to maintain basal synaptic transmission at the presynaptic terminal. We propose that glycolytic enzymes are closely apposed to ATP-dependent ion pumps on the presynaptic membrane. Our results indicate a novel mechanism for the effect of hypoglycemia on neurotransmission. Attenuated transmission likely results from a single presynaptic mechanism at reduced temperature: a slower, smaller AP, before and independent of any effect on synaptic vesicle release or receptor activity.
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Liu, Sheng, Veronica Bonalume, Qi Gao, et al. "Pre-Synaptic GABAA in NaV1.8+ Primary Afferents Is Required for the Development of Punctate but Not Dynamic Mechanical Allodynia following CFA Inflammation." Cells 11, no. 15 (2022): 2390. http://dx.doi.org/10.3390/cells11152390.
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Hypersensitivity to mechanical stimuli is a cardinal symptom of neuropathic and inflammatory pain. A reduction in spinal inhibition is generally considered a causal factor in the development of mechanical hypersensitivity after injury. However, the extent to which presynaptic inhibition contributes to altered spinal inhibition is less well established. Here, we used conditional deletion of GABAA in NaV1.8-positive sensory neurons (Scn10aCre;Gabrb3fl/fl) to manipulate selectively presynaptic GABAergic inhibition. Behavioral testing showed that the development of inflammatory punctate allodynia was mitigated in mice lacking pre-synaptic GABAA. Dorsal horn cellular circuits were visualized in single slices using stimulus-tractable dual-labelling of c-fos mRNA for punctate and the cognate c-Fos protein for dynamic mechanical stimulation. This revealed a substantial reduction in the number of cells activated by punctate stimulation in mice lacking presynaptic GABAA and an approximate 50% overlap of the punctate with the dynamic circuit, the relative percentage of which did not change following inflammation. The reduction in dorsal horn cells activated by punctate stimuli was equally prevalent in parvalbumin- and calretinin-positive cells and across all laminae I–V, indicating a generalized reduction in spinal input. In peripheral DRG neurons, inflammation following complete Freund’s adjuvant (CFA) led to an increase in axonal excitability responses to GABA, suggesting that presynaptic GABA effects in NaV1.8+ afferents switch from inhibition to excitation after CFA. In the days after inflammation, presynaptic GABAA in NaV1.8+ nociceptors constitutes an “open gate” pathway allowing mechanoreceptors responding to punctate mechanical stimulation access to nociceptive dorsal horn circuits.
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Khatri, Shailesh N., Wan-Chen Wu, Ying Yang, and Jason R. Pugh. "Direction of action of presynaptic GABAA receptors is highly dependent on the level of receptor activation." Journal of Neurophysiology 121, no. 5 (2019): 1896–905. http://dx.doi.org/10.1152/jn.00779.2018.
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Many synapses, including parallel fiber synapses in the cerebellum, express presynaptic GABAA receptors. However, reports of the functional consequences of presynaptic GABAA receptor activation are variable across synapses, from inhibition to enhancement of transmitter release. We find that presynaptic GABAA receptor function is bidirectional at parallel fiber synapses depending on GABA concentration and modulation of GABAA receptors in mice. Activation of GABAA receptors by low GABA concentrations enhances glutamate release, whereas activation of receptors by higher GABA concentrations inhibits release. Furthermore, blocking GABAB receptors reduces GABAA receptor currents and shifts presynaptic responses toward greater enhancement of release across a wide range of GABA concentrations. Conversely, enhancing GABAA receptor currents with ethanol or neurosteroids shifts responses toward greater inhibition of release. The ability of presynaptic GABAA receptors to enhance or inhibit transmitter release at the same synapse depending on activity level provides a new mechanism for fine control of synaptic transmission by GABA and may explain conflicting reports of presynaptic GABAA receptor function across synapses. NEW & NOTEWORTHY GABAA receptors are widely expressed at presynaptic terminals in the central nervous system. However, previous reports have produced conflicting results on the function of these receptors at different synapses. We show that presynaptic GABAA receptor function is strongly dependent on the level of receptor activation. Low levels of receptor activation enhance transmitter release, whereas higher levels of activation inhibit release at the same synapses. This provides a novel mechanism by which presynaptic GABAA receptors fine-tune synaptic transmission.
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Congar, Patrice, Annie Bergevin, and Louis-Eric Trudeau. "D2 Receptors Inhibit the Secretory Process Downstream From Calcium Influx in Dopaminergic Neurons: Implication of K+ Channels." Journal of Neurophysiology 87, no. 2 (2002): 1046–56. http://dx.doi.org/10.1152/jn.00459.2001.
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Dopaminergic (DAergic) neurons possess D2-like somatodendritic and terminal autoreceptors that modulate cellular excitability and dopamine (DA) release. The cellular and molecular processes underlying the rapid presynaptic inhibition of DA release by D2 receptors remain unclear. Using a culture system in which isolated DAergic neurons establish self-innervating synapses (“autapses”) that release both DA and glutamate, we studied the mechanism by which presynaptic D2 receptors inhibit glutamate-mediated excitatory postsynaptic currents (EPSCs). Action-potential evoked EPSCs were reversibly inhibited by quinpirole, a selective D2 receptor agonist. This inhibition was slightly reduced by the inward rectifier K+ channel blocker barium, largely prevented by the voltage-dependent K+channel blocker 4-aminopyridine, and completely blocked by their combined application. The lack of a residual inhibition of EPSCs under these conditions argues against the implication of a direct inhibition of presynaptic Ca2+ channels. To evaluate the possibility of a direct inhibition of the secretory process, spontaneous miniature EPSCs were evoked by the Ca2+ ionophore ionomycin. Ionomycin-evoked release was insensitive to cadmium and dramatically reduced by quinpirole, providing evidence for a direct inhibition of quantal release at a step downstream to Ca2+ influx through voltage-dependent Ca2+ channels. Surprisingly, this effect of quinpirole on ionomycin-evoked release was blocked by 4-aminopyridine. These results suggest that D2 receptor activation decreases neurotransmitter release from DAergic neurons through a presynaptic mechanism in which K+ channels directly inhibit the secretory process.