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.

scholarly journals Apoptosis and Necrosis Occur in Separate Neuronal Populations in Hippocampus and Cerebellum after Ischemia and Are Associated with Differential Alterations in Metabotropic Glutamate Receptor Signaling Pathways

2000 ◽  
Vol 20 (1) ◽  
pp. 153-167 ◽  
Author(s):  
Lee J. Martin ◽  
Frederick E. Sieber ◽  
Richard J. Traystman
Keyword(s):  
Signaling Pathways ◽  
Purkinje Cells ◽  
Cerebellar Cortex ◽  
Metabotropic Glutamate Receptors ◽  
Pyramidal Neurons ◽  
Metabotropic Glutamate Receptor ◽  
Pyramidal Cells ◽  
Granule Neurons ◽  
Metabotropic Glutamate ◽  
Cerebellar Purkinje Cells

It was evaluated whether postischemic neurodegeneration is apoptosis and occurs with alterations in phosphoinositide-linked metabotropic glutamate receptors (mGluRs) and their associated signaling pathways. A dog model of transient global incomplete cerebral ischemia was used. The CA1 pyramidal cells and cerebellar Purkinje cells underwent progressive delayed degeneration. By in situ end-labeling of DNA, death of CA1 and Purkinje cells was greater at 7 days than 1 day after ischemia, whereas death of granule neurons in dentate gyrus and cerebellar cortex was greater at 1 than at 7 days. Ultrastructurally, degenerating CA1 pyramidal neurons and cerebellar Purkinje cells were necrotic; in contrast, degenerating granule neurons were apoptotic. In agarose gels of regional DNA extracts, random DNA fragmentation coexisted with internucleosomal fragmentation. By immunoblotting of regional homogenates, mGluR1α, mGluR5, phospholipase Cβ (PLCβ), and Gαq/11 protein levels in hippocampus at 1 and 7 days after ischemia were similar to control levels, but in cerebellar cortex, mGluR1α and mGluR5 were decreased but PLCβ was increased. By immunocytochemistry, mGluR and PLCβ immunoreactivity dissipated in CA1 and cerebellar Purkinje cell/ molecular layers, whereas immunoreactivities for these proteins were enhanced in granule neurons. It was concluded that neuronal death after global ischemia exists as two distinct, temporally overlapping forms in hippocampus and cerebellum: necrosis of pyramidal neurons and Purkinje cells and apoptosis of granule neurons. Neuronal necrosis is associated with a loss of phosphoinositide-linked mGluR transduction proteins, whereas neuronal apoptosis occurs with increased mGluR signaling.

scholarly journals Numb deficiency in cerebellar Purkinje cells impairs synaptic expression of metabotropic glutamate receptor and motor coordination

2015 ◽  
Vol 112 (50) ◽  
pp. 15474-15479 ◽  
Author(s):  
Liang Zhou ◽  
Dong Yang ◽  
De-Juan Wang ◽  
Ya-Jun Xie ◽  
Jia-Huan Zhou ◽  
...  
Keyword(s):  
Cell Fate ◽  
Purkinje Cells ◽  
Glutamate Receptor ◽  
Motor Coordination ◽  
Metabotropic Glutamate Receptor ◽  
Constitutive Expression ◽  
Metabotropic Glutamate ◽  
Associated Proteins ◽  
Cerebellar Purkinje Cells

Protein Numb, first identified as a cell-fate determinant in Drosophila, has been shown to promote the development of neurites in mammals and to be cotransported with endocytic receptors in clathrin-coated vesicles in vitro. Nevertheless, its function in mature neurons has not yet been elucidated. Here we show that cerebellar Purkinje cells (PCs) express high levels of Numb during adulthood and that conditional deletion of Numb in PCs is sufficient to impair motor coordination despite maintenance of a normal cerebellar cyto-architecture. Numb proved to be critical for internalization and recycling of metabotropic glutamate 1 receptor (mGlu1) in PCs. A significant decrease of mGlu1 and an inhibition of long-term depression at the parallel fiber–PC synapse were observed in conditional Numb knockout mice. Indeed, the trafficking of mGlu1 induced by agonists was inhibited significantly in these mutants, but the expression of ionotropic glutamate receptor subunits and of mGlu1-associated proteins was not affected by the loss of Numb. Moreover, transient and persistent forms of mGlu1 plasticity were robustly induced in mutant PCs, suggesting that they do not require mGlu1 trafficking. Together, our data demonstrate that Numb is a regulator for constitutive expression and dynamic transport of mGlu1.

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.

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