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Christian Hansel - One of the best experts on this subject based on the ideXlab platform.
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muscarinic acetylcholine receptor activation blocks long term potentiation at cerebellar Parallel Fiber purkinje cell synapses via cannabinoid signaling
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Lorenzo Rinaldo, Christian HanselAbstract:Muscarinic acetylcholine receptors (mAChRs) are known to modulate synaptic plasticity in various brain areas. A signaling pathway triggered by mAChR activation is the production and release of endocannabinoids that bind to type 1 cannabinoid receptors (CB1R) located on synaptic terminals. Using whole-cell patch-clamp recordings from rat cerebellar slices, we have demonstrated that the muscarinic agonist oxotremorine-m (oxo-m) blocks the induction of presynaptic long-term potentiation (LTP) at Parallel Fiber (PF)–Purkinje cell synapses in a CB1R-dependent manner. Under control conditions, LTP was induced by delivering 120 PF stimuli at 8 Hz. In contrast, no LTP was observed when oxo-m was present during tetanization. PF-LTP was restored when the CB1R antagonist N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (AM251) was coapplied with oxo-m. Furthermore, the suppressive effect of oxo-m on PF-LTP was abrogated by the GDP analog GDP-β-S (applied intracellularly), the phospholipase C inhibitor U-73122, and the diacylglycerol lipase inhibitor tetrahydrolipstatin (THL), suggesting that cannabinoid synthesis results from the activation of Gq-coupled mAChRs present on Purkinje cells. The oxo-m–mediated suppression of LTP was also prevented in the presence of the M3 receptor antagonist DAU 5884, and was absent in M1/M3 receptor double-KO mice, identifying M3 receptors as primary oxo-m targets. Our findings allow for the possibility that cholinergic signaling in the cerebellum—which may result from long-term depression (LTD)-related disinhibition of cholinergic neurons in the vestibular nuclei—suppresses presynaptic LTP to prevent an up-regulation of transmitter release that opposes the reduction of postsynaptic responsiveness. This modulatory capacity of mAChR signaling could promote the functional penetrance of LTD.
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beta camkii controls the direction of plasticity at Parallel Fiber ndash purkinje cell synapses
Nature Neuroscience, 2009Co-Authors: Geeske M Van Woerden, Christian Hansel, Chris I De Zeeuw, Freek E Hoebeek, Zhenyu Gao, Raghavendra Y Nagaraja, Casper C Hoogenraad, Steven A KushnerAbstract:We found that betaCaMKII, the predominant CaMKII isoform of the cerebellum, is important for controlling the direction of plasticity at the Parallel Fiber-Purkinje cell synapse; a protocol that induced synaptic depression in wild-type mice resulted in synaptic potentiation in Camk2b knockout mice and vice versa. These findings provide us with unique experimental insight into the mechanisms that transduce graded calcium signals into either synaptic depression or potentiation.
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alcohol impairs long term depression at the cerebellar Parallel Fiber purkinje cell synapse
Journal of Neurophysiology, 2008Co-Authors: Amor Belmeguenai, John T. Weber, Chris I De Zeeuw, Paolo Botta, Mario Carta, Martijn M De Ruiter, Fernando C Valenzuela, Christian HanselAbstract:Acute alcohol consumption causes deficits in motor coordination and gait, suggesting an involvement of cerebellar circuits, which play a role in the fine adjustment of movements and in motor learning. It has previously been shown that ethanol modulates inhibitory transmission in the cerebellum and affects synaptic transmission and plasticity at excitatory climbing Fiber (CF) to Purkinje cell synapses. However, it has not been examined thus far how acute ethanol application affects long-term depression (LTD) and long-term potentiation (LTP) at excitatory Parallel Fiber (PF) to Purkinje cell synapses, which are assumed to mediate forms of cerebellar motor learning. To examine ethanol effects on PF synaptic transmission and plasticity, we performed whole cell patch-clamp recordings from Purkinje cells in rat cerebellar slices. We found that ethanol (50 mM) selectively blocked PF–LTD induction, whereas it did not change the amplitude of excitatory postsynaptic currents at PF synapses. In contrast, ethanol application reduced voltage-gated calcium currents and type 1 metabotropic glutamate receptor (mGluR1)–dependent responses in Purkinje cells, both of which are involved in PF–LTD induction. The selectivity of these effects is emphasized by the observation that ethanol did not impair PF–LTP and that PF–LTP could readily be induced in the presence of the group I mGluR antagonist AIDA or the mGluR1a antagonist LY367385. Taken together, these findings identify calcium currents and mGluR1-dependent signaling pathways as potential ethanol targets and suggest that an ethanol-induced blockade of PF–LTD could contribute to the motor coordination deficits resulting from alcohol consumption.
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synaptic memories upside down bidirectional plasticity at cerebellar Parallel Fiber purkinje cell synapses
Neuron, 2006Co-Authors: Henrik Jorntell, Christian HanselAbstract:Information storage in neural circuits depends on activity-dependent alterations in synaptic weights, such as long-term potentiation (LTP) and long-term depression (LTD). Bidirectional synaptic plasticity endows synapses with mechanisms for rapid reversibility, but it remains unclear how it correlates with reversibility in behavioral learning and whether there is a universal synaptic memory mechanism that operates similarly at all types of synapses. A recently discovered postsynaptic form of LTP at cerebellar Parallel Fiber (PF)-Purkinje cell (PC) synapses provides a reversal mechanism for PF-LTD and enables a fresh look at the implications of bidirectional plasticity in a brain structure that is particularly suitable to correlate cellular to behavioral learning events. Here, we will review recent studies that reveal unique properties of bidirectional cerebellar plasticity and suggest that the induction cascades for cerebellar LTP and LTD provide a mirror image of their counterparts at hippocampal synapses. We will also discuss how PF-LTP helps to explain reversibility observed in cerebellar motor learning.
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Bidirectional Parallel Fiber plasticity in the cerebellum under climbing Fiber control
Neuron, 2004Co-Authors: Michiel Coesmans, John T. Weber, Chris I De Zeeuw, Christian HanselAbstract:Cerebellar Parallel Fiber (PF)-Purkinje cell (PC) synapses can undergo postsynaptically expressed long-term depression (LTD) or long-term potentiation (LTP) depending on whether or not the climbing Fiber (CF) input is coactivated during tetanization. Here, we show that modifications of the postsynaptic calcium load using the calcium chelator BAPTA or photolytic calcium uncaging result in a reversal of the expected polarity of synaptic gain change. At higher concentrations, BAPTA blocks PF-LTP. These data indicate that PF-LTD requires a higher calcium threshold amplitude than PF-LTP induction and suggest that CF activity acts as a polarity switch by providing dendritic calcium transients. Moreover, previous CF-LTD induction changes the relative PF-LTD versus -LTP induction probability. These findings suggest that bidirectional cerebellar learning is governed by a calcium threshold rule operating "inverse" to the mechanism previously described at other glutamatergic synapses (BCM rule) and that the LTD/LTP induction probability is under heterosynaptic climbing Fiber control.
Chris I De Zeeuw - One of the best experts on this subject based on the ideXlab platform.
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nmdars in granule cells contribute to Parallel Fiber purkinje cell synaptic plasticity and motor learning
Proceedings of the National Academy of Sciences of the United States of America, 2021Co-Authors: Martijn Schonewille, Chris I De Zeeuw, Allison E Girasole, Philippe Rostaing, Caroline Mailheshamon, Annick Ayon, Alexandra B Nelson, Antoine Triller, Mariano CasadoAbstract:Long-term synaptic plasticity is believed to be the cellular substrate of learning and memory. Synaptic plasticity rules are defined by the specific complement of receptors at the synapse and the associated downstream signaling mechanisms. In young rodents, at the cerebellar synapse between granule cells (GC) and Purkinje cells (PC), bidirectional plasticity is shaped by the balance between transcellular nitric oxide (NO) driven by presynaptic N-methyl-D-aspartate receptor (NMDAR) activation and postsynaptic calcium dynamics. However, the role and the location of NMDAR activation in these pathways is still debated in mature animals. Here, we show in adult rodents that NMDARs are present and functional in presynaptic terminals where their activation triggers NO signaling. In addition, we find that selective genetic deletion of presynaptic, but not postsynaptic, NMDARs prevents synaptic plasticity at Parallel Fiber-PC (PF-PC) synapses. Consistent with this finding, the selective deletion of GC NMDARs affects adaptation of the vestibulo-ocular reflex. Thus, NMDARs presynaptic to PCs are required for bidirectional synaptic plasticity and cerebellar motor learning.
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nmdars in granule cells contribute to Parallel Fiber purkinje cell synaptic plasticity and motor learning
bioRxiv, 2021Co-Authors: Martijn Schonewille, Chris I De Zeeuw, Allison E Girasole, Philippe Rostaing, Caroline Mailheshamon, Annick Ayon, Alexandra B Nelson, Antoine Triller, Mariano CasadoAbstract:Abstract Long-term synaptic plasticity is believed to be the cellular substrate of learning and memory. Synaptic plasticity rules are defined by the specific complement of receptors at the synapse and the associated downstream signaling mechanisms. In young rodents, at the cerebellar synapse between granule cells (GC) and Purkinje cells (PC), bidirectional plasticity is shaped by the balance between transcellular nitric oxide (NO) driven by presynaptic NMDA receptor (NMDAR) activation and postsynaptic calcium dynamics. However, the role and the location of NMDAR activation in these pathways is still debated in mature animals. Here, we show in adult rodents that NMDARs are present and functional in presynaptic terminals where their activation triggers nitric oxide signaling. In addition, we find that selective genetic deletion of presynaptic, but not postsynaptic, NMDARs prevents synaptic plasticity at Parallel Fiber-Purkinje cell (PF-PC) synapses. Consistent with this finding, the selective deletion of GCs NMDARs affects adaptation of the vestibulo-ocular reflex. Thus, NMDARs presynaptic to PCs are required for bidirectional synaptic plasticity and cerebellar motor learning. Significance Statement Learning depends on synaptic plasticity. The signaling mechanisms that control induction of plasticity determine the learning rules at the specific synapse involved. Moreover, the relationship between the activity patterns of synaptic inputs and the type, direction, and level of plasticity induced may evolve during development. Here, we establish a key link between NMDA receptor activation presynaptic to cerebellar Purkinje cells, downstream signaling mechanisms, and the ability of adult animals to learn a cerebellar motor task.
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impact of Parallel Fiber to purkinje cell long term depression is unmasked in absence of inhibitory input
Science Advances, 2018Co-Authors: Henkjan Boele, Chris I De Zeeuw, S K E Koekkoek, Sasa Peter, Michiel Ten M Brinke, Lucas Verdonschot, Anna C H Ijpelaar, Dimitris RizopoulosAbstract:Pavlovian eyeblink conditioning has been used extensively to study the neural mechanisms underlying associative and motor learning. During this simple learning task, memory formation takes place at Purkinje cells in defined areas of the cerebellar cortex, which acquire a strong temporary suppression of their activity during conditioning. Yet, it is unknown which neuronal plasticity mechanisms mediate this suppression. Two potential mechanisms include long-term depression of Parallel Fiber to Purkinje cell synapses and feed-forward inhibition by molecular layer interneurons. We show, using a triple transgenic approach, that only concurrent disruption of both these suppression mechanisms can severely impair conditioning, highlighting that both processes can compensate for each other’s deficits.
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ablation of tfr1 in purkinje cells inhibits mglu1 trafficking and impairs motor coordination but not autistic like behaviors
The Journal of Neuroscience, 2017Co-Authors: Jiahuan Zhou, Lida Su, Lin Zhou, Xintai Wang, Liang Zhou, Fangxiao Xu, Hao Wang, Fuqiang Xu, Guiquan Chen, Chris I De ZeeuwAbstract:Group 1 metabotropic glutamate receptors (mGlu1/5s) are critical to synapse formation and participate in synaptic LTP and LTD in the brain. mGlu1/5 signaling alterations have been documented in cognitive impairment, neurodegenerative disorders, and psychiatric diseases, but underlying mechanisms for its modulation are not clear. Here, we report that transferrin receptor 1 (TFR1), a transmembrane protein of the clathrin complex, modulates the trafficking of mGlu1 in cerebellar Purkinje cells (PCs) from male mice. We show that conditional knock-out of TFR1 in PCs does not affect the cytoarchitecture of PCs, but reduces mGlu1 expression at synapses. This regulation by TFR1 acts in concert with that by Rab8 and Rab11, which modulate the internalization and recycling of mGlu1, respectively. TFR1 can bind to Rab proteins and facilitate their expression at synapses. PC ablation of TFR1 inhibits Parallel Fiber–PC LTD, whereas Parallel Fiber–LTP and PC intrinsic excitability are not affected. Finally, we demonstrate that PC ablation of TFR1 impairs motor coordination, but does not affect social behaviors in mice. Together, these findings underscore the importance of TFR1 in regulating mGlu1 trafficking and suggest that mGlu1- and mGlu1-dependent Parallel Fiber–LTD are associated with regulation of motor coordination, but not autistic behaviors. SIGNIFICANCE STATEMENT Group 1 metabotropic glutamate receptor (mGlu1/5) signaling alterations have been documented in cognitive impairment, neurodegenerative disorders, and psychiatric diseases. Recent work suggests that altered mGlu1 signaling in Purkinje cells (PCs) may be involved in not only motor learning, but also autistic-like behaviors. We find that conditional knock-out of transferrin receptor 1 (TFR1) in PCs reduces synaptic mGlu1 by tethering Rab8 and Rab11 in the cytosol. PC ablation of TFR1 inhibits Parallel Fiber–PC LTD, whereas Parallel Fiber–PC LTP and PC intrinsic excitability are intact. Motor coordination is impaired, but social behaviors are normal in TFR1flox/flox;pCP2-cre mice. Our data reveal a new regulator for trafficking and synaptic expression of mGlu1 and suggest that mGlu1-dependent LTD is associated with motor coordination, but not autistic-like behaviors.
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T-type channel blockade impairs long-term potentiation at the Parallel Fiber-Purkinje cell synapse and cerebellar learning
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Guy Bouvier, Chris I De Zeeuw, Martijn Schonewille, Mariano Casado, Arnaud Arabo, Laure Rondi-reig, Clement Lena, Anne FeltzAbstract:Ca(V)3.1 T-type channels are abundant at the cerebellar synapse between Parallel Fibers and Purkinje cells where they contribute to synaptic depolarization. So far, no specific physiological function has been attributed to these channels neither as charge carriers nor more specifically as Ca2+ carriers. Here we analyze their incidence on synaptic plasticity, motor behavior, and cerebellar motor learning, comparing WT animals and mice where T-type channel function has been abolished either by gene deletion or by acute pharmacological blockade. At the cellular level, we show that Ca(V)3.1 channels are required for long-term potentiation at Parallel Fiber-Purkinje cell synapses. Moreover, basal simple spike discharge of the Purkinje cell in KO mice is modified. Acute or chronic T-type current blockade results in impaired motor performance in particular when a good body balance is required. Because motor behavior integrates reflexes and past memories of learned behavior, this suggests impaired learning. Indeed, subjecting the KO mice to a vestibulo-ocular reflex phase reversal test reveals impaired cerebellum-dependent motor learning. These data identify a role of low-voltage activated calcium channels in synaptic plasticity and establish a role for Ca(V)3.1 channels in cerebellar learning.
Masamitsu Iino - One of the best experts on this subject based on the ideXlab platform.
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regulation of long term depression and climbing Fiber territory by glutamate receptor δ2 at Parallel Fiber synapses through its c terminal domain in cerebellar purkinje cells
The Journal of Neuroscience, 2007Co-Authors: Takeshi Uemura, Sho Kakizawa, Masamitsu Iino, Masahiko Watanabe, Kenji Sakimura, Miwako Yamasaki, Masayoshi MishinaAbstract:Glutamate receptor (GluR) δ2 selectively expressed in cerebellar Purkinje cells (PCs) plays key roles in long-term depression (LTD) induction at Parallel Fiber (PF)–PC synapses, motor learning, the matching and connection of PF–PC synapses in developing and adult cerebella, the elimination of multiple climbing Fibers (CFs) during development, and the regulation of CF territory on PCs. However, it remains unsolved how GluRδ2 regulates cerebellar synaptic plasticity, PF–PC synapse formation, and CF wiring. One possible signaling mechanism through GluRδ2 is signaling by protein–protein interactions. The C-terminal region of GluRδ2 contains at least three domains for protein–protein interactions. The PDZ (postsynaptic density-95/Discs large/zona occludens 1)-binding domain at the C terminal, named as the T site, interacts with several postsynaptic density proteins. Here, we generated GluRδ2ΔT mice carrying mutant GluRδ2 lacking the T site. There were no significant differences in the amount of receptor proteins at synapses, histological features, and the fine structures of PF–PC synapses between wild-type and GluRδ2ΔT mice. However, LTD induction at PF–PC synapses and improvement in the accelerating rotarod test were impaired in GluRδ2ΔT mice. Furthermore, CF territory expanded distally and ectopic innervation of CFs occurred at distal dendrites in GluRδ2ΔT mice, but the elimination of surplus CF innervation at proximal dendrites appeared to proceed normally. These results suggest that the C-terminal T site of GluRδ2 is essential for LTD induction and the regulation of CF territory but is dispensable for PF–PC synapse formation and the elimination of surplus CFs at proximal dendrites during development.
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postsynaptic inositol 1 4 5 trisphosphate signaling maintains presynaptic function of Parallel Fiber purkinje cell synapses via bdnf
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Kazuharu Furutani, Yohei Okubo, Sho Kakizawa, Masamitsu IinoAbstract:The maintenance of synaptic functions is essential for neuronal information processing, but cellular mechanisms that maintain synapses in the adult brain are not well understood. Here, we report an activity-dependent maintenance mechanism of Parallel Fiber (PF)–Purkinje cell (PC) synapses in the cerebellum. When postsynaptic metabotropic glutamate receptor (mGluR) or inositol 1,4,5-trisphosphate (IP3) signaling was chronically inhibited in vivo, PF–PC synaptic strength decreased because of a decreased transmitter release probability. The same effects were observed when PF activity was inhibited in vivo by the suppression of NMDA receptor-mediated inputs to granule cells. PF–PC synaptic strength similarly decreased after the in vivo application of an antibody against brain-derived neurotrophic factor (BDNF). Furthermore, the weakening of synaptic connection caused by the blockade of mGluR–IP3 signaling was reversed by the in vivo application of BDNF. These results indicate that a signaling cascade comprising PF activity, postsynaptic mGluR–IP3 signaling and subsequent BDNF signaling maintains presynaptic functions in the mature cerebellum.
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cross talk between metabotropic and ionotropic glutamate receptor mediated signaling in Parallel Fiber induced inositol 1 4 5 trisphosphate production in cerebellar purkinje cells
The Journal of Neuroscience, 2004Co-Authors: Yohei Okubo, Sho Kakizawa, Kenzo Hirose, Masamitsu IinoAbstract:In many excitatory glutamatergic synapses, both ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs) are closely distributed on the postsynaptic membrane. However, the functional significance of the close distribution of the two types of glutamate receptors has not been fully clarified. In this study, we examined the functional interaction between iGluR and mGluR at Parallel Fiber (PF)--> Purkinje cell synapses in the generation of inositol 1,4,5-trisphosphate (IP3), a key second messenger that regulates many important cellular functions. We visualized local IP3 dynamics in Purkinje cells using the green fluorescent protein-tagged pleckstrin homology domain (GFP-PHD) as a fluorescent IP3 probe. Purkinje cells were transduced with Sindbis virus encoding GFP-PHD and imaged with a two-photon laser scanning microscope. Translocation of GFP-PHD from the plasma membrane to the cytoplasm attributable to an increase in IP3 concentration was observed on PF stimulation in fine dendrites of Purkinje cells. Surprisingly, this PF-induced IP3 production was blocked not only by the group I mGluR antagonist but also by the AMPA receptor (AMPAR) antagonist. The PF-induced IP3 production was blocked by either the inhibition of G-protein activation by GDP-betaS or intracellular Ca2+ buffering by BAPTA. These results show that IP3 production is mediated cooperatively by group I mGluR and AMPAR through G-protein activation and Ca2+ influx at PF--> Purkinje cell synapses, identifying the robust cross talk between iGluR and mGluR for the generation of IP3 signals.
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cross talk between metabotropic and ionotropic glutamate receptor mediated signaling in Parallel Fiber induced inositol 1 4 5 trisphosphate production in cerebellar purkinje cells
The Journal of Neuroscience, 2004Co-Authors: Yohei Okubo, Sho Kakizawa, Kenzo Hirose, Masamitsu IinoAbstract:In many excitatory glutamatergic synapses, both ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs) are closely distributed on the postsynaptic membrane. However, the functional significance of the close distribution of the two types of glutamate receptors has not been fully clarified. In this study, we examined the functional interaction between iGluR and mGluR at Parallel Fiber (PF)→ Purkinje cell synapses in the generation of inositol 1,4,5-trisphosphate (IP 3 ), a key second messenger that regulates many important cellular functions. We visualized local IP 3 dynamics in Purkinje cells using the green fluorescent protein-tagged pleckstrin homology domain (GFP-PHD) as a fluorescent IP 3 probe. Purkinje cells were transduced with Sindbis virus encoding GFP-PHD and imaged with a two-photon laser scanning microscope. Translocation of GFP-PHD from the plasma membrane to the cytoplasm attributable to an increase in IP 3 concentration was observed on PF stimulation in fine dendrites of Purkinje cells. Surprisingly, this PF-induced IP 3 production was blocked not only by the group I mGluR antagonist but also by the AMPA receptor (AMPAR) antagonist. The PF-induced IP 3 production was blocked by either the inhibition of G-protein activation by GDP-βS or intracellular Ca 2+ buffering by BAPTA. These results show that IP 3 production is mediated cooperatively by group I mGluR and AMPAR through G-protein activation and Ca 2+ influx at PF→ Purkinje cell synapses, identifying the robust cross talk between iGluR and mGluR for the generation of IP 3 signals.
James M Bower - One of the best experts on this subject based on the ideXlab platform.
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3d electron microscopic reconstruction of segments of rat cerebellar purkinje cell dendrites receiving ascending and Parallel Fiber granule cell synaptic inputs
The Journal of Comparative Neurology, 2009Co-Authors: Angelica V Esquivel, James M BowerAbstract:Growing physiological evidence suggests that there are functional differences between synapses made by the ascending and Parallel Fiber segments of the granule axon on cerebellar Purkinje cells. Supporting this view, our previous electron microscopic studies suggested that these synapses also contacted different regions of the Purkinje cell dendrite, and in particular that ascending segment synapses are made exclusively on the smallest diameter Purkinje cell dendrites. In the current study we used serial electron microscopic techniques to reconstruct Purkinje cell dendritic segments up to almost 10 mum in length. Using a combination of anatomical and immunological labeling techniques we identified the ascending or Parallel Fiber origins of the excitatory synaptic inputs onto dendritic spines, as well as the location of inhibitory synapses made directly on the dendritic shaft. The results confirmed that there are regions of the Purkinje cell dendrite receiving exclusively ascending or Parallel Fiber synapses and that ascending segment synapses are only found on small-diameter dendrites. In addition, we describe for the first time small-diameter dendritic regions contacted by both types of excitatory synapses. While our data suggest that the majority of inhibitory inputs to the Purkinje cell tree are associated with Parallel Fiber synaptic inputs, we also found inhibitory inputs on dendritic regions with mixed ascending and Parallel Fiber inputs, or exclusively Parallel Fiber inputs. The finding that ascending and Parallel Fiber inputs can be segregated on the Purkinje cell dendritic tree provides further evidence that these excitatory granule cell synaptic inputs may be functionally distinct.
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the organization of cerebellar cortical circuitry revisited implications for function
Annals of the New York Academy of Sciences, 2002Co-Authors: James M BowerAbstract:: For more than 35 years there has been experimental evidence that Parallel Fiber activity does not generate the beams of activated Purkinje cells hypothesized on the basis of cortical anatomy and assumed by most theories of cerebellar cortical function. This paper first reviews the evidence for and against the Parallel Fiber beam hypothesis, and then discusses the findings of our recent experimental and model-based investigations intended to better understand Parallel Fiber effects on Purkinje cells. A principal conclusion of these studies is that the excitatory effects of Parallel Fibers on Purkinje cell dendrites are modulating and must be considered in the context of a balancing inhibitory influence provided by molecular layer interneurons to these same dendrites. It is proposed that this association of excitation and inhibition can account for the lack of beam-like effects on Purkinje cells. The paper concludes by considering the consequences of this new interpretation of cerebellar cortical circuitry for current theories of cerebellar function.
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modulatory effects of Parallel Fiber and molecular layer interneuron synaptic activity on purkinje cell responses to ascending segment input a modeling study
Journal of Computational Neuroscience, 2002Co-Authors: Fidel Santamaria, Dieter Jaeger, E De Schutter, James M BowerAbstract:Based on anatomical, physiological, and model-based studies, it has been proposed that synapses associated with the ascending segment of granule cell axons provide the principle excitatory drive on Purkinje cells which is then modulated by the more numerous Parallel Fiber synapses. In this study we have evaluated this idea using a detailed compartmental model of a cerebellar Purkinje cell by providing identical ascending segment synaptic inputs during different levels of random Parallel Fiber and molecular interneuron input. Results suggest that background inputs from Parallel Fibers and molecular layer interneurons can have a substantial effect on the response of Purkinje cells to ascending segment inputs. Interestingly, these effects are not reflected in the average firing rate of the Purkinje cell and are thus entirely dendritic in effect. These results are considered in the context of the known segregated spatial distribution of the Parallel Fibers and ascending segment synapses and a new hypothesis concerning the functional organization of cerebellar cortical circuitry.
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ascending granule cell axon an important component of cerebellar cortical circuitry
The Journal of Comparative Neurology, 1999Co-Authors: Girija Gundappasulur, Erik De Schutter, James M BowerAbstract:Physiologic evidence suggests that local activation of the cerebellar granule cell layer produces a much more restricted spatial activation of overlying Purkinje cells than would be expected from the Parallel Fiber system. These results have led to the suggestion that synapses associated with the ascending granule cell axon may provide a large, direct, excitatory input to Purkinje cells, whereas Parallel Fiber synapses may be more modulatory in nature. In the current experiments, serial electron microscopy was used to reconstruct synapses associated with these two segments of the granule cell axons in the cerebellar cortex of albino rats. The results indicate that there are significantly more presynaptic vesicles in ascending segment synapses than in Parallel Fiber synapses. Furthermore, a first-order linear regression analysis revealed positive correlations between all measures of pre- and postsynaptic morphology for Parallel Fibers, but not for ascending segment synapses. Perhaps most surprisingly, serial reconstructions of postsynaptic spines and their associated dendrites demonstrated that spines contacted by ascending segment synapses are located exclusively on the smallest diameter distal regions of the Purkinje cell dendrites, whereas Parallel Fiber synapses are found exclusively on intermediate- and large-diameter regions of the spiny branchlets. Based on two independent calculations, we estimate that 20% of the granule cell synapses onto a Purkinje cell are actually made by the ascending segment. By using computer simulations of a single Purkinje cell dendrite, we have also demonstrated that synchronous activation of these distal ascending segment inputs could produce a substantial somatic response. Taken together, these results suggest that the two different regions of granule cell axons may play very different physiologic roles in cerebellar cortex.
David J Linden - One of the best experts on this subject based on the ideXlab platform.
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phosphorylation of rim1α by pka triggers presynaptic long term potentiation at cerebellar Parallel Fiber synapses
Cell, 2003Co-Authors: Thomas C Sudhof, Gyorgy Lonart, Susanne Schoch, Pascal S Kaeser, Jenny C Larkin, David J LindenAbstract:Presynaptic activation of protein kinase A (PKA) induces LTP in cerebellar Parallel Fiber synapses. Presynaptic LTP is known to require the active zone protein RIM1α, but the underlying induction mechanism remains unclear. We now show that PKA directly phosphorylates RIM1α at two sites. Using paired recordings from cultured cerebellar granule and Purkinje neurons, we demonstrate that LTP is absent in neurons from RIM1α KO mice but is rescued by presynaptic expression of RIM1α. Mutant RIM1α lacking the N-terminal phosphorylation site is unable to rescue LTP in RIM1α knockout neurons but selectively suppresses LTP in wild-type neurons. Our findings suggest that PKA-mediated phosphorylation of the active zone protein RIM1α at a single N-terminal site induces presynaptic LTP.
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beyond Parallel Fiber ltd the diversity of synaptic and non synaptic plasticity in the cerebellum
Nature Neuroscience, 2001Co-Authors: Christian Hansel, David J Linden, Egidio DangeloAbstract:Beyond Parallel Fiber LTD: the diversity of synaptic and non-synaptic plasticity in the cerebellum
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beyond Parallel Fiber ltd the diversity of synaptic and non synaptic plasticity in the cerebellum
Nature Neuroscience, 2001Co-Authors: Christian Hansel, David J Linden, Egidio DangeloAbstract:In recent years, it has become clear that motor learning, as revealed by associative eyelid conditioning and adaptation of the vestibulo-ocular reflex, contributes to the well-established cerebellar functions of sensorimotor integration and control. Long-term depression of the Parallel Fiber-Purkinje cell synapse (which is often called 'cerebellar LTD') is a cellular phenomenon that has been suggested to underlie these forms of learning. However, it is clear that Parallel Fiber LTD, by itself, cannot account for all the properties of cerebellar motor learning. Here we review recent electrophysiological experiments that have described a rich variety of use-dependent plasticity in cerebellum, including long-term potentiation (LTP) and LTD of excitatory and inhibitory synapses, and persistent modulation of intrinsic neuronal excitability. Finally, using associative eyelid conditioning as an example, we propose some ideas about how these cellular phenomena might function and interact to endow the cerebellar circuit with particular computational and mnemonic properties.
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long term depression of the cerebellar climbing Fiber purkinje neuron synapse
Neuron, 2000Co-Authors: Christian Hansel, David J LindenAbstract:In classic Marr-Albus-Ito models of cerebellar function, coactivation of the climbing Fiber (CF) synapse, which provides massive, invariant excitation of Purkinje neurons (coding the unconditioned stimulus), together with a graded Parallel Fiber synaptic array (coding the conditioned stimulus) leads to long-term depression (LTD) of Parallel Fiber-Purkinje neuron synapses, underlying production of a conditioned response. Here, we show that the supposedly invariant CF synapse can also express LTD. Brief 5 Hz stimulation of the CF resulted in a sustained depression of CF EPSCs that did not spread to neighboring Parallel Fiber synapses. Like Parallel Fiber LTD, CF LTD required postsynaptic Ca2+ elevation, activation of group 1 mGluRs, and activation of PKC. CF LTD is potentially relevant for models of cerebellar motor control and learning and the developmental conversion from multiple to single CF innervation of Purkinje neurons.
