Calcium Dynamics and Electrophysiological Properties of Cerebellar Purkinje Cells in SCA1 Transgenic Mice

2001 ◽  
Vol 85 (4) ◽  
pp. 1750-1760 ◽  
Author(s):  
Takafumi Inoue ◽  
Xi Lin ◽  
Kristi A. Kohlmeier ◽  
Harry T. Orr ◽  
Huda Y. Zoghbi ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Purkinje Cells ◽  
Metabotropic Glutamate Receptor ◽  
Membrane Resistance ◽  
Spinocerebellar Ataxia Type ◽  
Patch Clamp Recording ◽  
Experimental Conditions ◽  
Cerebellar Purkinje Cells ◽  
Electrical Responses

Cerebellar Purkinje cells (PCs) from spinocerebellar ataxia type 1 (SCA1) transgenic mice develop dendritic and somatic atrophy with age. Inositol 1,4,5-trisphosphate receptor type 1 and the sarco/endoplasmic reticulum Ca2+ ATPase pump, which regulate [Ca2+]i, are expressed at lower levels in these cells compared with the levels in cells from wild-type (WT) mice. To examine PCs in SCA1 mice, we used whole-cell patch clamp recording combined with fluorometric [Ca2+]i and [Na+]i measurements in cerebellar slices. PCs in SCA1 mice had Na+ spikes, Ca2+ spikes, climbing fiber (CF) electrical responses, parallel fiber (PF) electrical responses, and metabotropic glutamate receptor (mGluR)-mediated, PF-evoked Ca2+ release from intracellular stores that were qualitatively similar to those recorded from WT mice. Under our experimental conditions, it was easier to evoke the mGluR-mediated secondary [Ca2+]i increase in SCA1 PCs. The membrane resistance of SCA1 PCs was 3.3 times higher than that of WT cells, which correlated with the 1.7 times smaller cell body size. Most SCA1 PCs (but not WT) had a delayed onset (about 50–200 ms) to Na+ spike firing induced by current injection. This delay was increased by hyperpolarizing prepulses and was eliminated by 4-aminopyridine, which suggests that this delay was due to enhancement of the A-like K+ conductance in the SCA1 PCs. In response to CF stimulation, most PCs in mutant and WT mice had rapid, widespread [Ca2+]i changes that recovered in <200 ms. Some SCA1 PCs showed a slow, localized, secondary Ca2+ transient following the initial CF Ca2+ transient, which may reflect release of Ca2+ from intracellular stores. Thus, with these exceptions, the basic physiological properties of mutant PCs are similar to those of WT neurons, even with dramatic alteration of their morphology and downregulation of Ca2+ handling molecules.

scholarly journals Progress in pathogenesis studies of spinocerebellar ataxia type 1

1999 ◽  
Vol 354 (1386) ◽  
pp. 1079-1081 ◽  
Author(s):  
Christopher J. Cummings ◽  
Harry T. Orr ◽  
Huda Y. Zoghbi
Keyword(s):  
Transgenic Mice ◽  
Purkinje Cell ◽  
Purkinje Cells ◽  
Nuclear Localization ◽  
Hela Cells ◽  
Protein Misfolding ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 1 ◽  
Cerebellar Purkinje Cells

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited disorder characterized by progressive loss of coordination, motor impairment and the degeneration of cerebellar Purkinje cells, spinocerebellar tracts and brainstem nuclei. Many dominantly inherited neurodegenerative diseases share the mutational basis of SCA1: the expansion of a translated CAG repeat coding for glutamine. Mice lacking ataxin-1 display learning deficits and altered hippocampal synaptic plasticity but none of the abnormalities seen in human SCA1; mice expressing ataxin-1 with an expanded CAG tract (82 glutamine residues), however, develop Purkinje cell pathology and ataxia. These results suggest that mutant ataxin-1 gains a novel function that leads to neuronal degeneration. This novel function might involve aberrant interaction(s) with cell-specific protein(s), which in turn might explain the selective neuronal pathology. Mutant ataxin-1 interacts preferentially with a leucine-rich acidic nuclear protein that is abundantly expressed in cerebellar Purkinje cells and other brain regions affected in SCA1. Immunolocalization studies in affected neurons of patients and SCA1 transgenic mice showed that mutant ataxin-1 localizes to a single, ubiquitin-positive nuclear inclusion (NI) that alters the distribution of the proteasome and certain chaperones. Further analysis of NIs in transfected HeLa cells established that the proteasome and chaperone proteins co-localize with ataxin-1 aggregates. Moreover, overexpression of the chaperone HDJ-2/HSDJ in HeLa cells decreased ataxin-1 aggregation, suggesting that protein misfolding might underlie NI formation. To assess the importance of the nuclear localization of ataxin-1 and its role in SCA1 pathogenesis, two lines of transgenic mice were generated. In the first line, the nuclear localization signal was mutated so that full-length mutant ataxin-1 would remain in the cytoplasm; mice from this line did not develop any ataxia or pathology. This suggests that mutant ataxin-1 is pathogenic only in the nucleus. To assess the role of the aggregates, transgenic mice were generated with mutant ataxin-1 without the self-association domain (SAD) essential for aggregate formation. These mice developed ataxia and Purkinje cell abnormalities similar to those seen in SCA1 transgenic mice carrying full-length mutant ataxin-1, but lacked NIs. The nuclear milieu is thus a critical factor in SCA1 pathogenesis, but large NIs are not needed to initiate pathogenesis. They might instead be downstream of the primary pathogenic steps. Given the accumulated evidence, we propose the following model for SCA1 pathogenesis: expansion of the polyglutamine tract alters the conformation of ataxin-1, causing it to misfold. This in turn leads to aberrant protein interactions. Cell specificity is determined by the cell-specific proteins interacting with ataxin-1. Submicroscopic protein aggregation might occur because of protein misfolding, and those aggregates become detectable as NIs as the disease advances. Proteasome redistribution to the NI might contribute to disease progression by disturbing proteolysis and subsequent vital cellular functions.

scholarly journals Type-1 metabotropic glutamate receptor signaling in cerebellar Purkinje cells in health and disease

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 416 ◽  
Author(s):  
Masanobu Kano ◽  
Takaki Watanabe
Keyword(s):  
Purkinje Cells ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Synaptic Response ◽  
Coordination Control ◽  
Metabotropic Glutamate ◽  
Health And Disease ◽  
Output Neurons ◽  
Cerebellar Purkinje Cells

The cerebellum is a brain structure involved in coordination, control, and learning of movements, as well as certain aspects of cognitive function. Purkinje cells are the sole output neurons from the cerebellar cortex and therefore play crucial roles in the overall function of the cerebellum. The type-1 metabotropic glutamate receptor (mGluR1) is a key “hub” molecule that is critically involved in the regulation of synaptic wiring, excitability, synaptic response, and synaptic plasticity of Purkinje cells. In this review, we aim to highlight how mGluR1 controls these events in Purkinje cells. We also describe emerging evidence that altered mGluR1 signaling in Purkinje cells underlies cerebellar dysfunctions in several clinically relevant mouse models of human ataxias.

scholarly journals Type-1 metabotropic glutamate receptor in cerebellar Purkinje cells: a key molecule responsible for long-term depression, endocannabinoid signalling and synapse elimination

2008 ◽  
Vol 363 (1500) ◽  
pp. 2173-2186 ◽  
Author(s):  
Masanobu Kano ◽  
Kouichi Hashimoto ◽  
Toshihide Tabata
Keyword(s):  
Signal Transduction ◽  
Purkinje Cells ◽  
Glutamate Receptor ◽  
Molecular Mechanisms ◽  
Metabotropic Glutamate Receptor ◽  
Long Term Depression ◽  
Metabotropic Glutamate ◽  
Cerebellar Purkinje Cells

The cerebellum is a brain structure involved in the coordination, control and learning of movements, and elucidation of its function is an important issue. Japanese scholars have made seminal contributions in this field of neuroscience. Electrophysiological studies of the cerebellum have a long history in Japan since the pioneering works by Ito and Sasaki. Elucidation of the basic circuit diagram of the cerebellum in the 1960s was followed by the construction of cerebellar network theories and finding of their neural correlates in the 1970s. A theoretically predicted synaptic plasticity, long-term depression (LTD) at parallel fibre to Purkinje cell synapse, was demonstrated experimentally in 1982 by Ito and co-workers. Since then, Japanese neuroscientists from various disciplines participated in this field and have made major contributions to elucidate molecular mechanisms underlying LTD. An important pathway for LTD induction is type-1 metabotropic glutamate receptor (mGluR1) and its downstream signal transduction in Purkinje cells. Sugiyama and co-workers demonstrated the presence of mGluRs and Nakanishi and his pupils identified the molecular structures and functions of the mGluR family. Moreover, the authors contributed to the discovery and elucidation of several novel functions of mGluR1 in cerebellar Purkinje cells. mGluR1 turned out to be crucial for the release of endocannabinoid from Purkinje cells and the resultant retrograde suppression of transmitter release. It was also found that mGluR1 and its downstream signal transduction in Purkinje cells are indispensable for the elimination of redundant synapses during post-natal cerebellar development. This article overviews the seminal works by Japanese neuroscientists, focusing on mGluR1 signalling in cerebellar Purkinje cells.

scholarly journals Extracellular S100β Disrupts Bergman Glia Morphology and Synaptic Transmission in Cerebellar Purkinje Cells

2019 ◽  
Vol 9 (4) ◽  
pp. 80 ◽  
Author(s):  
Belozor ◽  
Yakovleva ◽  
Potapenko ◽  
Shuvaev ◽  
Smolnikova ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Purkinje Cells ◽  
Pathological Process ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 1 ◽  
Cortical Organization ◽  
Neurodegenerative Process ◽  
Cerebellar Purkinje Cells ◽  
And Function

Astrogliosis is a pathological process that affects the density, morphology, and function of astrocytes. It is a common feature of brain trauma, autoimmune diseases, and neurodegeneration including spinocerebellar ataxia type 1 (SCA1), a poorly understood neurodegenerative disease. S100β is a Ca2+ binding protein. In SCA1, excessive excretion of S100β by reactive astrocytes and its uptake by Purkinje cells has been demonstrated previously. Under pathological conditions, excessive extracellular concentration of S100β stimulates the production of proinflammatory cytokines and induces apoptosis. We modeled astrogliosis by S100β injections into cerebellar cortex in mice. Injections of S100β led to significant changes in Bergmann glia (BG) cortical organization and affected their processes. S100β also changed morphology of the Purkinje cells (PCs), causing a significant reduction in the dendritic length. Moreover, the short-term synaptic plasticity and depolarization-induced suppression of synaptic transmission were disrupted after S100β injections. We speculate that these effects are the result of Ca2+-chelating properties of S100β protein. In summary, exogenous S100β induced astrogliosis in cerebellum could lead to neuronal dysfunction, which resembles a natural neurodegenerative process. We suggest that astrocytes play an essential role in SCA1 pathology, and that astrocytic S100β is an important contributor to this process.

scholarly journals Characterization of starvation-induced autophagy in cerebellar Purkinje cells of pHluorin-mKate2-human LC3B transgenic mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Juan Alejandro Oliva Trejo ◽  
Isei Tanida ◽  
Chigure Suzuki ◽  
Soichiro Kakuta ◽  
Norihiro Tada ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Purkinje Cells ◽  
Cerebellar Purkinje Cells

scholarly journals mGlu1 receptor mediates homeostatic control of intrinsic excitability through Ih in cerebellar Purkinje cells

2016 ◽  
Vol 115 (5) ◽  
pp. 2446-2455 ◽  
Author(s):  
Hyun Geun Shim ◽  
Sung-Soo Jang ◽  
Dong Cheol Jang ◽  
Yunju Jin ◽  
Wonseok Chang ◽  
...  
Keyword(s):  
Purkinje Cells ◽  
Neuronal Activity ◽  
Metabotropic Glutamate Receptor ◽  
Activity Level ◽  
Network Activity ◽  
Firing Rates ◽  
Metabotropic Glutamate ◽  
Gated Channel ◽  
Intrinsic Plasticity ◽  
Cerebellar Purkinje Cells

Homeostatic intrinsic plasticity is a cellular mechanism for maintaining a stable neuronal activity level in response to developmental or activity-dependent changes. Type 1 metabotropic glutamate receptor (mGlu1 receptor) has been widely known to monitor neuronal activity, which plays a role as a modulator of intrinsic and synaptic plasticity of neurons. Whether mGlu1 receptor contributes to the compensatory adjustment of Purkinje cells (PCs), the sole output of the cerebellar cortex, in response to chronic changes in excitability remains unclear. Here, we demonstrate that the mGlu1 receptor is involved in homeostatic intrinsic plasticity through the upregulation of the hyperpolarization-activated current ( Ih) in cerebellar PCs. This plasticity was prevented by inhibiting the mGlu1 receptor with Bay 36–7620, an mGlu1 receptor inverse agonist, but not with CPCCOEt, a neutral antagonist. Chronic inactivation with tetrodotoxin (TTX) increased the components of Ih in the PCs, and ZD 7288, a hyperpolarization-activated cyclic nucleotide-gated channel selective inhibitor, fully restored reduction of firing rates in the deprived neurons. The homeostatic elevation of Ih was also prevented by BAY 36–7620, but not CPCCOEt. Furthermore, KT 5720, a blocker of protein kinase A (PKA), prevented the effect of TTX reducing the evoked firing rates, indicating the reduction in excitability of PCs due to PKA activation. Our study shows that both the mGlu1 receptor and the PKA pathway are involved in the homeostatic intrinsic plasticity of PCs after chronic blockade of the network activity, which provides a novel understanding on how cerebellar PCs can preserve the homeostatic state under activity-deprived conditions.

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