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Volker Haucke - One of the best experts on this subject based on the ideXlab platform.
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Neuronal Autophagy Regulates Presynaptic Neurotransmission by Controlling the Axonal Endoplasmic Reticulum.
Neuron, 2020Co-Authors: Marijn Kuijpers, Dmytro Puchkov, Gaga Kochlamazashvili, Alexander Stumpf, Aarti Swaminathan, Max Thomas Lucht, Eberhard Krause, Tanja Maritzen, Dietmar Schmitz, Volker HauckeAbstract:Summary Neurons are known to rely on autophagy for removal of defective proteins or organelles to maintain synaptic Neurotransmission and counteract neurodegeneration. In spite of its importance for neuronal health, the physiological substrates of neuronal autophagy in the absence of proteotoxic challenge have remained largely elusive. We use knockout mice conditionally lacking the essential autophagy protein ATG5 and quantitative proteomics to demonstrate that loss of neuronal autophagy causes selective accumulation of tubular endoplasmic reticulum (ER) in axons, resulting in increased excitatory Neurotransmission and compromised postnatal viability in vivo. The gain in excitatory Neurotransmission is shown to be a consequence of elevated calcium release from ER stores via ryanodine receptors accumulated in axons and at presynaptic sites. We propose a model where neuronal autophagy controls axonal ER calcium stores to regulate Neurotransmission in healthy neurons and in the brain.
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vesicular synaptobrevin vamp2 levels guarded by ap180 control efficient Neurotransmission
Neuron, 2015Co-Authors: Seong Joo Koo, Dmytro Puchkov, Gaga Kochlamazashvili, Benjamin R. Rost, Niclas Gimber, Martin Lehmann, Georgi Tadeus, Jan Schmoranzer, Christian Rosenmund, Volker HauckeAbstract:Summary Neurotransmission depends on synaptic vesicle (SV) exocytosis driven by soluble N -ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex formation of vesicular synaptobrevin/VAMP2 (Syb2). Exocytic fusion is followed by endocytic SV membrane retrieval and the high-fidelity reformation of SVs. Syb2 is the most abundant SV protein with 70 copies per SV, yet, one to three Syb2 molecules appear to be sufficient for basal exocytosis. Here we demonstrate that loss of the Syb2-specific endocytic adaptor AP180 causes a moderate activity-dependent reduction of vesicular Syb2 levels, defects in SV reformation, and a corresponding impairment of Neurotransmission that lead to excitatory/inhibitory imbalance, epileptic seizures, and premature death. Further reduction of Syb2 levels in AP180 −/− / Syb2 +/− mice results in perinatal lethality, whereas Syb2 +/− mice partially phenocopy loss of AP180, indicating that reduced vesicular Syb2 levels underlie the observed defects in Neurotransmission. Thus, a large vesicular Syb2 pool maintained by AP180 is crucial to sustain efficient Neurotransmission and SV reformation.
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Vesicular Synaptobrevin/VAMP2 Levels Guarded by AP180 Control Efficient Neurotransmission
Neuron, 2015Co-Authors: Seong Joo Koo, Dmytro Puchkov, Gaga Kochlamazashvili, Benjamin R. Rost, Niclas Gimber, Martin Lehmann, Georgi Tadeus, Jan Schmoranzer, Christian Rosenmund, Volker HauckeAbstract:Summary Neurotransmission depends on synaptic vesicle (SV) exocytosis driven by soluble N -ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex formation of vesicular synaptobrevin/VAMP2 (Syb2). Exocytic fusion is followed by endocytic SV membrane retrieval and the high-fidelity reformation of SVs. Syb2 is the most abundant SV protein with 70 copies per SV, yet, one to three Syb2 molecules appear to be sufficient for basal exocytosis. Here we demonstrate that loss of the Syb2-specific endocytic adaptor AP180 causes a moderate activity-dependent reduction of vesicular Syb2 levels, defects in SV reformation, and a corresponding impairment of Neurotransmission that lead to excitatory/inhibitory imbalance, epileptic seizures, and premature death. Further reduction of Syb2 levels in AP180 −/− / Syb2 +/− mice results in perinatal lethality, whereas Syb2 +/− mice partially phenocopy loss of AP180, indicating that reduced vesicular Syb2 levels underlie the observed defects in Neurotransmission. Thus, a large vesicular Syb2 pool maintained by AP180 is crucial to sustain efficient Neurotransmission and SV reformation.
David Mendelowitz - One of the best experts on this subject based on the ideXlab platform.
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5-Hydroxytryptamine 1A/7 and 4 Receptors Differentially Prevent Opioid-Induced Inhibition of Brain Stem Cardiorespiratory Function
2016Co-Authors: Xin Wang, Christopher Gorini, Olga Dergacheva, Harriet Kamendi, David MendelowitzAbstract:Abstract—Opioids evoke respiratory depression, bradycardia, and reduced respiratory sinus arrhythmia, whereas serotonin (5-HT) agonists stimulate respiration and cardiorespiratory interactions. This study tested whether serotonin agonists can prevent the inhibitory effects of opioids on cardiorespiratory function. Spontaneous and rhythmic inspiratory-related activity and -aminobutyric acid (GABA) Neurotransmission to premotor parasympathetic cardioinhibitory neurons in the nucleus ambiguus were recorded simultaneously in an in vitro thick slice preparation. The -opioid agonist fentanyl inhibited respiratory frequency. The 5-hydroxytryptamine 1A/7 receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin increased respiratory frequency by itself and also prevented the fentanyl-induced respiratory depression. The 5-hydroxytryptamine 4 agonist BIMU-8 did not by itself change inspiratory activity but prevented the -opioid– mediated respiratory depression. Both spontaneous and inspiratory-evoked GABAergic Neurotransmission to cardiac vagal neurons were inhibited by fentanyl. 8-Hydroxy-2-(di-n-propylamino)tetralin inhibited spontaneous but not inspiratory-evoked GABAergic activity to parasympathetic cardiac neurons. However, 8-hydroxy-2-(di-n-propylamino)tetralin differentially altered the opioid-mediated depression of inspiratory-evoked GABAergic activity but did not change the opioid-induced reduction in spontaneous GABAergic Neurotransmission. In contrast, BIMU-8 did not alter GABAergic Neurotransmission to cardiac vagal neurons by itself but prevented the fentanyl depression of both spontaneous and inspiratory-elicited GABAergic Neurotransmission to cardiac vagal neurons. In the presence of tetrodotoxin
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5 ht2 receptors modulate excitatory Neurotransmission to cardiac vagal neurons within the nucleus ambiguus evoked during and after hypoxia
Neuroscience, 2009Co-Authors: Olga Dergacheva, Christopher Gorini, Heather Jameson, Harriet Kamendi, Xin Wang, Ramon A Pinol, J G Frank, Mary Rachael Lovettbarr, David MendelowitzAbstract:To examine the role of 5-HT2 receptors in the central cardiorespiratory network, and in particular the respiratory modulation of parasympathetic activity to the heart, we used an in vitro medullary slice that allowed simultaneous examination of rhythmic inspiratory-related activity recorded from hypoglossal rootlet and excitatory inspiratory-related Neurotransmission to cardioinhibitory vagal neurons (CVNs) within the nucleus ambiguus (NA). Focal application of ketanserin, a 5-HT2 receptor antagonist, did not significantly alter the frequency of spontaneous excitatory postsynaptic excitatory currents (EPSCs) in CVNs in control conditions. However, ketanserin diminished spontaneous excitatory Neurotransmission to CVNs during hypoxia. The inhibitory action of ketanserin was on 5-HT3 mediated EPSCs during hypoxia since these responses were blocked by the 5-HT3 receptor antagonist ondansetron. In addition, a robust inspiratory-related excitatory Neurotransmission was recruited during recovery from hypoxia. Focal application of ketanserin during this posthypoxia period evoked a significant augmentation of the frequency of inspiratory-related, but not spontaneous EPSCs in CVNs. This excitatory effect of ketanserin was prevented by application of the purinergic receptor blocker pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS). These results demonstrate 5-HT2 receptors differentially modulate excitatory Neurotransmission to CVNs during and after hypoxia. Activation of 5-HT2 receptors acts to maintain excitatory Neurotransmission to CVNs during hypoxia, likely via presynaptic facilitation of 5-HT3 receptor-mediated Neurotransmission to CVNs. However, activation of 5HT2 receptors diminishes the subsequent inspiratory-related excitatory Neurotransmission to CVNs that is recruited during the recovery from hypoxia likely exerting an inhibitory action on inspiratory-related purinergic signaling.
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Purinergic P2X receptors facilitate inhibitory GABAergic and glycinergic Neurotransmission to cardiac vagal neurons in the nucleus ambiguus.
Brain research, 2008Co-Authors: Heather Jameson, Ramon A Pinol, David MendelowitzAbstract:This study examined whether adenosine 5’-triphosphate (ATP) modulated inhibitory glycinergic and GABAergic Neurotransmission to cardiac vagal neurons. Inhibitory activity to cardiac vagal neurons was isolated and examined using whole-cell patch-clamp recordings in an in vitro brain slice preparation in rats. ATP (100 µM) evoked increases in the frequency of glycinergic and GABAergic miniature inhibitory postsynaptic currents (mIPSCs) in cardiac vagal neurons which were blocked by the broad P2 receptor antagonist pyridoxal-phosphate-6-azophenyl-2’,4’-disulphonic acid (100 µM). Application of the P2Y agonists uridine triphosphate (15 µM) and adenosine 5'-0-(Z-thiodiphosphate) (60 µM) did not enhance inhibitory Neurotransmission to cardiac vagal neurons however, application of the selective P2X receptor agonist, α, β –methylene ATP (100 µM), increased glycinergic and GABAergic mIPSC Neurotransmission to cardiac vagal neurons. The increase in inhibitory Neurotransmission evoked by α, β–methylene ATP was abolished by the selective P2X receptor antagonist 2',3'-O-(2,4,6-Trinitrophenyl) adenosine 5'-triphosphate (100 µM) indicating P2X receptors enhance the release of inhibitory neurotransmitters to cardiac neurons. The voltage gated calcium channel blocker cadmium chloride did not alter the evoked increase in inhibitory mIPSCs. This work demonstrates that P2X receptor activation enhances inhibitory Neurotransmission to parasympathetic cardiac vagal neurons and demonstrates an important functional role for ATP mediated purinergic signaling to cardiac vagal neurons.
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Purinergic P2X Receptors Mediate Excitatory Transmission to Cardiac Vagal Neurons in the Nucleus Ambiguus After Hypoxia
Hypertension (Dallas Tex. : 1979), 2007Co-Authors: Kathleen J. Griffioen, Christopher Gorini, Heather Jameson, David MendelowitzAbstract:Challenges such as hypoxia elicit a powerful response from both the central cardiovascular and respiratory neuronal networks. Recent work indicates that purinergic Neurotransmission in the brain stem is an important modulator of central respiratory network responses to hypoxia. This study tests whether alterations in purinergic Neurotransmission extend beyond respiratory responses to hypoxia and also mediates respiratory inputs to cardiac vagal neurons. To examine central cardiorespiratory responses to hypoxia, we used an in vitro medullary slice that allows simultaneous examination of rhythmic respiratory-related activity and synaptic Neurotransmission to cardioinhibitory vagal neurons. Here we show that P2X receptor activation mediates respiratory-related excitatory Neurotransmission to parasympathetic cardiac vagal neurons, the dominant control of heart rate. These data demonstrate a critical functional role for adenosine 5'-triphosphate-mediated purinergic signaling in facilitating respiratory-related excitatory Neurotransmission to cardiac vagal neurons after hypoxia.
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propofol modulates γ aminobutyric acid mediated inhibitory Neurotransmission to cardiac vagal neurons in the nucleus ambiguus
Anesthesiology, 2004Co-Authors: Xin Wang, Zheng Gui Huang, Allison Gold, Evguenia Bouairi, Cory Evans, Michael C Andresen, David MendelowitzAbstract:Background: Although it is well recognized that anesthetics modulate the central control of cardiorespiratory homeostasis, the cellular mechanisms by which anesthetics alter cardiac parasympathetic activity are poorly understood. One common site of action of anesthetics is inhibitory Neurotransmission. This study investigates the effect of propofol on γ-aminobutyric acid-mediated (GABAergic) and glycinergic Neurotransmission to cardiac parasympathetic neurons. Methods: Cardiac parasympathetic neurons were identified in vitro by the presence of a retrograde fluorescent tracer, and spontaneous GABAergic and glycinergic synaptic currents were examined using whole cell patch clamp techniques. Results: Propofol at concentrations of 1.0 μM and greater significantly (P < 0.05) increased the duration and decay time of spontaneous GABAergic inhibitory postsynaptic currents. To determine whether the action of propofol was at presynaptic or postsynaptic sites, tetrodotoxin was applied to isolate miniature inhibitory postsynaptic currents. Propofol at concentrations of 1.0 μM and greater significantly (P < 0.05) prolonged the decay time and duration of miniature inhibitory postsynaptic currents, indicating that propofol directly alters GABAergic Neurotransmission at a postsynaptic site. Propofol at high concentrations (≥ 50 μM) also inhibited the frequency of both GABAergic inhibitory postsynaptic currents and miniature inhibitory postsynaptic currents. Propofol at concentrations up to 50 μM had no effect on glycinergic Neurotransmission. Conclusions: Propofol may vary heart rate by modulating GABAergic Neurotransmission to cardiac parasympathetic neurons. At clinically relevant concentrations (≥ 1.0 μM), propofol facilitated GABAergic responses in cardiac vagal neurons by increasing decay time, which would increase inhibition of cardioinhibitory cardiac vagal neurons and evoke an increase in heart rate. At higher supraclinical concentrations (≥ 50 μM), propofol inhibits GABAergic Neurotransmission to cardiac vagal neurons, which would evoke a decrease in heart rate.
Dmytro Puchkov - One of the best experts on this subject based on the ideXlab platform.
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Neuronal Autophagy Regulates Presynaptic Neurotransmission by Controlling the Axonal Endoplasmic Reticulum.
Neuron, 2020Co-Authors: Marijn Kuijpers, Dmytro Puchkov, Gaga Kochlamazashvili, Alexander Stumpf, Aarti Swaminathan, Max Thomas Lucht, Eberhard Krause, Tanja Maritzen, Dietmar Schmitz, Volker HauckeAbstract:Summary Neurons are known to rely on autophagy for removal of defective proteins or organelles to maintain synaptic Neurotransmission and counteract neurodegeneration. In spite of its importance for neuronal health, the physiological substrates of neuronal autophagy in the absence of proteotoxic challenge have remained largely elusive. We use knockout mice conditionally lacking the essential autophagy protein ATG5 and quantitative proteomics to demonstrate that loss of neuronal autophagy causes selective accumulation of tubular endoplasmic reticulum (ER) in axons, resulting in increased excitatory Neurotransmission and compromised postnatal viability in vivo. The gain in excitatory Neurotransmission is shown to be a consequence of elevated calcium release from ER stores via ryanodine receptors accumulated in axons and at presynaptic sites. We propose a model where neuronal autophagy controls axonal ER calcium stores to regulate Neurotransmission in healthy neurons and in the brain.
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vesicular synaptobrevin vamp2 levels guarded by ap180 control efficient Neurotransmission
Neuron, 2015Co-Authors: Seong Joo Koo, Dmytro Puchkov, Gaga Kochlamazashvili, Benjamin R. Rost, Niclas Gimber, Martin Lehmann, Georgi Tadeus, Jan Schmoranzer, Christian Rosenmund, Volker HauckeAbstract:Summary Neurotransmission depends on synaptic vesicle (SV) exocytosis driven by soluble N -ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex formation of vesicular synaptobrevin/VAMP2 (Syb2). Exocytic fusion is followed by endocytic SV membrane retrieval and the high-fidelity reformation of SVs. Syb2 is the most abundant SV protein with 70 copies per SV, yet, one to three Syb2 molecules appear to be sufficient for basal exocytosis. Here we demonstrate that loss of the Syb2-specific endocytic adaptor AP180 causes a moderate activity-dependent reduction of vesicular Syb2 levels, defects in SV reformation, and a corresponding impairment of Neurotransmission that lead to excitatory/inhibitory imbalance, epileptic seizures, and premature death. Further reduction of Syb2 levels in AP180 −/− / Syb2 +/− mice results in perinatal lethality, whereas Syb2 +/− mice partially phenocopy loss of AP180, indicating that reduced vesicular Syb2 levels underlie the observed defects in Neurotransmission. Thus, a large vesicular Syb2 pool maintained by AP180 is crucial to sustain efficient Neurotransmission and SV reformation.
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Vesicular Synaptobrevin/VAMP2 Levels Guarded by AP180 Control Efficient Neurotransmission
Neuron, 2015Co-Authors: Seong Joo Koo, Dmytro Puchkov, Gaga Kochlamazashvili, Benjamin R. Rost, Niclas Gimber, Martin Lehmann, Georgi Tadeus, Jan Schmoranzer, Christian Rosenmund, Volker HauckeAbstract:Summary Neurotransmission depends on synaptic vesicle (SV) exocytosis driven by soluble N -ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex formation of vesicular synaptobrevin/VAMP2 (Syb2). Exocytic fusion is followed by endocytic SV membrane retrieval and the high-fidelity reformation of SVs. Syb2 is the most abundant SV protein with 70 copies per SV, yet, one to three Syb2 molecules appear to be sufficient for basal exocytosis. Here we demonstrate that loss of the Syb2-specific endocytic adaptor AP180 causes a moderate activity-dependent reduction of vesicular Syb2 levels, defects in SV reformation, and a corresponding impairment of Neurotransmission that lead to excitatory/inhibitory imbalance, epileptic seizures, and premature death. Further reduction of Syb2 levels in AP180 −/− / Syb2 +/− mice results in perinatal lethality, whereas Syb2 +/− mice partially phenocopy loss of AP180, indicating that reduced vesicular Syb2 levels underlie the observed defects in Neurotransmission. Thus, a large vesicular Syb2 pool maintained by AP180 is crucial to sustain efficient Neurotransmission and SV reformation.
Gaga Kochlamazashvili - One of the best experts on this subject based on the ideXlab platform.
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Neuronal Autophagy Regulates Presynaptic Neurotransmission by Controlling the Axonal Endoplasmic Reticulum.
Neuron, 2020Co-Authors: Marijn Kuijpers, Dmytro Puchkov, Gaga Kochlamazashvili, Alexander Stumpf, Aarti Swaminathan, Max Thomas Lucht, Eberhard Krause, Tanja Maritzen, Dietmar Schmitz, Volker HauckeAbstract:Summary Neurons are known to rely on autophagy for removal of defective proteins or organelles to maintain synaptic Neurotransmission and counteract neurodegeneration. In spite of its importance for neuronal health, the physiological substrates of neuronal autophagy in the absence of proteotoxic challenge have remained largely elusive. We use knockout mice conditionally lacking the essential autophagy protein ATG5 and quantitative proteomics to demonstrate that loss of neuronal autophagy causes selective accumulation of tubular endoplasmic reticulum (ER) in axons, resulting in increased excitatory Neurotransmission and compromised postnatal viability in vivo. The gain in excitatory Neurotransmission is shown to be a consequence of elevated calcium release from ER stores via ryanodine receptors accumulated in axons and at presynaptic sites. We propose a model where neuronal autophagy controls axonal ER calcium stores to regulate Neurotransmission in healthy neurons and in the brain.
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vesicular synaptobrevin vamp2 levels guarded by ap180 control efficient Neurotransmission
Neuron, 2015Co-Authors: Seong Joo Koo, Dmytro Puchkov, Gaga Kochlamazashvili, Benjamin R. Rost, Niclas Gimber, Martin Lehmann, Georgi Tadeus, Jan Schmoranzer, Christian Rosenmund, Volker HauckeAbstract:Summary Neurotransmission depends on synaptic vesicle (SV) exocytosis driven by soluble N -ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex formation of vesicular synaptobrevin/VAMP2 (Syb2). Exocytic fusion is followed by endocytic SV membrane retrieval and the high-fidelity reformation of SVs. Syb2 is the most abundant SV protein with 70 copies per SV, yet, one to three Syb2 molecules appear to be sufficient for basal exocytosis. Here we demonstrate that loss of the Syb2-specific endocytic adaptor AP180 causes a moderate activity-dependent reduction of vesicular Syb2 levels, defects in SV reformation, and a corresponding impairment of Neurotransmission that lead to excitatory/inhibitory imbalance, epileptic seizures, and premature death. Further reduction of Syb2 levels in AP180 −/− / Syb2 +/− mice results in perinatal lethality, whereas Syb2 +/− mice partially phenocopy loss of AP180, indicating that reduced vesicular Syb2 levels underlie the observed defects in Neurotransmission. Thus, a large vesicular Syb2 pool maintained by AP180 is crucial to sustain efficient Neurotransmission and SV reformation.
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Vesicular Synaptobrevin/VAMP2 Levels Guarded by AP180 Control Efficient Neurotransmission
Neuron, 2015Co-Authors: Seong Joo Koo, Dmytro Puchkov, Gaga Kochlamazashvili, Benjamin R. Rost, Niclas Gimber, Martin Lehmann, Georgi Tadeus, Jan Schmoranzer, Christian Rosenmund, Volker HauckeAbstract:Summary Neurotransmission depends on synaptic vesicle (SV) exocytosis driven by soluble N -ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex formation of vesicular synaptobrevin/VAMP2 (Syb2). Exocytic fusion is followed by endocytic SV membrane retrieval and the high-fidelity reformation of SVs. Syb2 is the most abundant SV protein with 70 copies per SV, yet, one to three Syb2 molecules appear to be sufficient for basal exocytosis. Here we demonstrate that loss of the Syb2-specific endocytic adaptor AP180 causes a moderate activity-dependent reduction of vesicular Syb2 levels, defects in SV reformation, and a corresponding impairment of Neurotransmission that lead to excitatory/inhibitory imbalance, epileptic seizures, and premature death. Further reduction of Syb2 levels in AP180 −/− / Syb2 +/− mice results in perinatal lethality, whereas Syb2 +/− mice partially phenocopy loss of AP180, indicating that reduced vesicular Syb2 levels underlie the observed defects in Neurotransmission. Thus, a large vesicular Syb2 pool maintained by AP180 is crucial to sustain efficient Neurotransmission and SV reformation.
Seong Joo Koo - One of the best experts on this subject based on the ideXlab platform.
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vesicular synaptobrevin vamp2 levels guarded by ap180 control efficient Neurotransmission
Neuron, 2015Co-Authors: Seong Joo Koo, Dmytro Puchkov, Gaga Kochlamazashvili, Benjamin R. Rost, Niclas Gimber, Martin Lehmann, Georgi Tadeus, Jan Schmoranzer, Christian Rosenmund, Volker HauckeAbstract:Summary Neurotransmission depends on synaptic vesicle (SV) exocytosis driven by soluble N -ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex formation of vesicular synaptobrevin/VAMP2 (Syb2). Exocytic fusion is followed by endocytic SV membrane retrieval and the high-fidelity reformation of SVs. Syb2 is the most abundant SV protein with 70 copies per SV, yet, one to three Syb2 molecules appear to be sufficient for basal exocytosis. Here we demonstrate that loss of the Syb2-specific endocytic adaptor AP180 causes a moderate activity-dependent reduction of vesicular Syb2 levels, defects in SV reformation, and a corresponding impairment of Neurotransmission that lead to excitatory/inhibitory imbalance, epileptic seizures, and premature death. Further reduction of Syb2 levels in AP180 −/− / Syb2 +/− mice results in perinatal lethality, whereas Syb2 +/− mice partially phenocopy loss of AP180, indicating that reduced vesicular Syb2 levels underlie the observed defects in Neurotransmission. Thus, a large vesicular Syb2 pool maintained by AP180 is crucial to sustain efficient Neurotransmission and SV reformation.
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Vesicular Synaptobrevin/VAMP2 Levels Guarded by AP180 Control Efficient Neurotransmission
Neuron, 2015Co-Authors: Seong Joo Koo, Dmytro Puchkov, Gaga Kochlamazashvili, Benjamin R. Rost, Niclas Gimber, Martin Lehmann, Georgi Tadeus, Jan Schmoranzer, Christian Rosenmund, Volker HauckeAbstract:Summary Neurotransmission depends on synaptic vesicle (SV) exocytosis driven by soluble N -ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex formation of vesicular synaptobrevin/VAMP2 (Syb2). Exocytic fusion is followed by endocytic SV membrane retrieval and the high-fidelity reformation of SVs. Syb2 is the most abundant SV protein with 70 copies per SV, yet, one to three Syb2 molecules appear to be sufficient for basal exocytosis. Here we demonstrate that loss of the Syb2-specific endocytic adaptor AP180 causes a moderate activity-dependent reduction of vesicular Syb2 levels, defects in SV reformation, and a corresponding impairment of Neurotransmission that lead to excitatory/inhibitory imbalance, epileptic seizures, and premature death. Further reduction of Syb2 levels in AP180 −/− / Syb2 +/− mice results in perinatal lethality, whereas Syb2 +/− mice partially phenocopy loss of AP180, indicating that reduced vesicular Syb2 levels underlie the observed defects in Neurotransmission. Thus, a large vesicular Syb2 pool maintained by AP180 is crucial to sustain efficient Neurotransmission and SV reformation.
