Abstract:Metabotropic glutamate receptors type 1 (mGluR1s) are required for a normal function of the mammalian brain. They are particularly important for synaptic signaling and plasticity in the cerebellum. Unlike ionotropic glutamate receptors that mediate rapid synaptic transmission, mGluR1s produce in cerebellar Purkinje cells a complex postsynaptic response consisting of two distinct signal components, namely a local dendritic calcium signal and a slow excitatory postsynaptic potential. The basic mechanisms underly… Show more
“…Similar to the mGluR1-mediated calcium transients, SCA2 PNs exhibited significantly larger EPSCs as compared to WT PNs across stimulus strengths (Figure 4B). Notably, larger EPSCs are not simply a consequence of increased calcium mobilization as intracellular calcium increases are not required for activation of the TRPC3 channel (Dzubay and Otis, 2002; Hartmann et al, 2008, Hartmann et al, 2011Hartmann et al, 2011Hartmann et al, 2011). Thus, these results suggest a comprehensive increase in mGluR1-mediated signaling, possibly due to some positive feedback occurring early in the signal transduction cascade.10.7554/eLife.26377.005Figure 4.Synaptic mGluR1 EPSCs are significantly larger in SCA2 PNs.( A and B ) Slow mGluR1 EPSCs in response to 5 and 10 pulse, 100 Hz stimuli applied to PFs.…”
Metabotropic glutamate receptor 1 (mGluR1) function in Purkinje neurons (PNs) is essential for cerebellar development and for motor learning and altered mGluR1 signaling causes ataxia. Downstream of mGluR1, dysregulation of calcium homeostasis has been hypothesized as a key pathological event in genetic forms of ataxia but the underlying mechanisms remain unclear. We find in a spinocerebellar ataxia type 2 (SCA2) mouse model that calcium homeostasis in PNs is disturbed across a broad range of physiological conditions. At parallel fiber synapses, mGluR1-mediated excitatory postsynaptic currents (EPSCs) and associated calcium transients are increased and prolonged in SCA2 PNs. In SCA2 PNs, enhanced mGluR1 function is prevented by buffering [Ca2+] at normal resting levels while in wildtype PNs mGluR1 EPSCs are enhanced by elevated [Ca2+]. These findings demonstrate a deleterious positive feedback loop involving elevated intracellular calcium and enhanced mGluR1 function, a mechanism likely to contribute to PN dysfunction and loss in SCA2.DOI:
http://dx.doi.org/10.7554/eLife.26377.001
“…Similar to the mGluR1-mediated calcium transients, SCA2 PNs exhibited significantly larger EPSCs as compared to WT PNs across stimulus strengths (Figure 4B). Notably, larger EPSCs are not simply a consequence of increased calcium mobilization as intracellular calcium increases are not required for activation of the TRPC3 channel (Dzubay and Otis, 2002; Hartmann et al, 2008, Hartmann et al, 2011Hartmann et al, 2011Hartmann et al, 2011). Thus, these results suggest a comprehensive increase in mGluR1-mediated signaling, possibly due to some positive feedback occurring early in the signal transduction cascade.10.7554/eLife.26377.005Figure 4.Synaptic mGluR1 EPSCs are significantly larger in SCA2 PNs.( A and B ) Slow mGluR1 EPSCs in response to 5 and 10 pulse, 100 Hz stimuli applied to PFs.…”
Metabotropic glutamate receptor 1 (mGluR1) function in Purkinje neurons (PNs) is essential for cerebellar development and for motor learning and altered mGluR1 signaling causes ataxia. Downstream of mGluR1, dysregulation of calcium homeostasis has been hypothesized as a key pathological event in genetic forms of ataxia but the underlying mechanisms remain unclear. We find in a spinocerebellar ataxia type 2 (SCA2) mouse model that calcium homeostasis in PNs is disturbed across a broad range of physiological conditions. At parallel fiber synapses, mGluR1-mediated excitatory postsynaptic currents (EPSCs) and associated calcium transients are increased and prolonged in SCA2 PNs. In SCA2 PNs, enhanced mGluR1 function is prevented by buffering [Ca2+] at normal resting levels while in wildtype PNs mGluR1 EPSCs are enhanced by elevated [Ca2+]. These findings demonstrate a deleterious positive feedback loop involving elevated intracellular calcium and enhanced mGluR1 function, a mechanism likely to contribute to PN dysfunction and loss in SCA2.DOI:
http://dx.doi.org/10.7554/eLife.26377.001
“…For TRPC3 in cerebellar Purkinje cells, a PLC-independent gating mechanism relies on the small GTP-binding protein Rho and subsequent phospholipase D activation (Glitsch, 2010). TRPC channels are known to be redundantly activated and appear to be located at a point of intersection of diverse signaling pathways (reviewed in (Hartmann et al, 2011)). Moreover, TRPC channels in neurons are part of multi-protein postsynaptic signaling complexes that also contain neurotransmitter receptors, including the NMDAR (reviewed in (Ambudkar et al, 2006)).…”
TRPC channels are widely expressed throughout the nervous system including the olfactory bulb where their function is largely unknown. Here we describe their contribution to central synaptic processing at the reciprocal mitral and tufted cell - granule cell microcircuit, the most abundant synapse of the mammalian olfactory bulb. Suprathreshold activation of the synapse causes sodium action potentials in mouse granule cells and a subsequent long-lasting depolarization (LLD) linked to a global dendritic postsynaptic calcium signal recorded with two-photon laser scanning microscopy. These signals are not observed after action potentials evoked by current injection in the same cells. The LLD persists in the presence of group I metabotropic glutamate receptor antagonists but is entirely absent from granule cells deficient for the NMDA receptor subunit NR1. Moreover, both depolarization and Ca2+ rise are sensitive to the blockade of NMDA receptors. The LLD and the accompanying Ca2+ rise are also absent in granule cells from mice deficient for both TRPC channel subtypes 1 and 4, whereas the deletion of either TRPC1 or TRPC4 results in only a partial reduction of the LLD. Recordings from mitral cells in the absence of both subunits reveal a reduction of asynchronous neurotransmitter release from the granule cells during recurrent inhibition. We conclude that TRPC1 and TRPC4 can be activated downstream of NMDA receptor activation and contribute to slow synaptic transmission in the olfactory bulb, including the calcium dynamics required for asynchronous release from the granule cell spine.
“…; Hartmann et al . ), were disrupted in PCs of SCA1 mice. Furthermore, fast confocal Ca 2+ imaging revealed that PCs in SCA1 mice exhibit reduced mGluR1‐mediated dendritic Ca 2+ signals, which were not detected in a previous widefield fluorescence imaging study (Inoue et al .…”
Key pointsr Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by a gene defect, leading to movement disorder such as cerebellar ataxia.r It remains largely unknown which functional defect contributes to the cerebellar ataxic phenotype in SCA1.r In this study, we report progressive dysfunction of metabotropic glutamate receptor (mGluR) signalling, which leads to smaller slow synaptic responses, reduced dendritic Ca 2+ signals and impaired synaptic plasticity at cerebellar synapses, in the early disease stage of SCA1 model mice.r We also show that enhancement of mGluR signalling by a clinically available drug, baclofen, leads to improvement of motor performance in SCA1 mice. r SCA1 is an incurable disease with no effective treatment, and our results may provide mechanistic grounds for targeting mGluRs and a novel drug therapy with baclofen to treat SCA1 patients in the future.Abstract Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease that presents with cerebellar ataxia and motor learning defects. Previous studies have indicated that the pathology of SCA1, as well as other ataxic diseases, is related to signalling pathways mediated by the metabotropic glutamate receptor type 1 (mGluR1), which is indispensable for proper motor coordination and learning. However, the functional contribution of mGluR signalling to SCA1 pathology is unclear. In the present study, we show that SCA1 model mice develop a functional impairment of mGluR signalling which mediates slow synaptic responses, dendritic Ca 2+ signals, and short-and long-term synaptic plasticity at parallel fibre (PF)-Purkinje cell (PC) synapses in a progressive manner from the early disease stage (5 postnatal weeks) prior to PC death. Notably, impairment of mGluR-mediated dendritic Ca 2+ signals linearly correlated with a reduction of PC capacitance (cell surface area) in disease progression. Enhancement of mGluR signalling by baclofen, a clinically available GABA B receptor agonist, led to an improvement of motor performance in SCA1 mice and the improvement lasted ß1 week after a single application of baclofen. Moreover, the restoration of motor performance in baclofen-treated SCA1 mice matched the functional recovery of mGluR-mediated slow synaptic currents and mGluR-dependent short-and long-term synaptic plasticity. These results suggest that impairment of synaptic mGluR cascades is one of the important contributing factors to cerebellar ataxia in early and middle stages of SCA1 pathology, and that modulation of mGluR signalling by baclofen or other clinical interventions may be therapeutic targets to treat SCA1. , human Ataxin-1 with 76 uninterrupted glutamine repeats; BDNF, brainderived neurotrophic factor; Calbindin, calbindin D-28k; C57BL/6 mice, C57 black 6 mice; CF, climbing fibre; CPCCOEt, 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylate ethyl ester; ER, endoplasmic reticulum; D-AP5, D-(-)-2-amino-5-phosphonopentanoic acid; GFP, green fluorescent protein; GPCR, G-protein-coupled rec...
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