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16 results on '"Zhai, Shenyu"'

3. Striatal Kir2 [K.sup.+] channel inhibition mediates the antidyskinetic effects of amantadine

Author

Shen, Weixing, Ren, Wenjie, Zhai, Shenyu, Yang, Ben, Vanoye, Carlos G., Mitra, Ananya, George, Alfred L., Jr., and Surmeier, D. James

Subjects
Movement disorders -- Analysis, N-methyl-D-aspartate -- Analysis, Aspartate -- Analysis, Glutamate -- Analysis, Amantadine, Neurons, Antiparkinson agents, Diseases, Health care industry
Abstract

Levodopa-induced dyskinesia (LID) poses a significant health care challenge for Parkinson's disease (PD) patients. Amantadine is currently the only drug proven to alleviate LID. Although its efficacy in treating LID is widely assumed to be mediated by blockade of N-methyl-D-aspartate (NMDA) glutamate receptors, our experiments demonstrate that at therapeutically relevant concentrations, amantadine preferentially blocks inward-rectifying 1C channel type 2 (Kir2) channels in striatal spiny projection neurons (SPNs)--not NMDA receptors. In so doing, amantadine enhances dendritic integration of excitatory synaptic potentials in SPNs and enhances--not antagonizes--the induction of long-term potentiation (LTP) at excitatory, axospinous synapses. Taken together, our studies suggest that the alleviation of LID in PD patients is mediated by diminishing the disparity in the excitability of direct- and indirect-pathway SPNs in the on state, rather than by disrupting LTP induction. This insight points to a pharmacological approach that could be used to effectively ameliorate LID and improve the quality of life for PD patients., Introduction Parkinson's disease (PD) is the second most common neurodegenerative disease (1, 2). The cardinal motor symptoms of PD are caused by the degeneration of dopaminergic neurons in the substantia [...]

Published
2020
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8. CalDAG-GEFI mediates striatal cholinergic modulation of dendritic excitability, synaptic plasticity and psychomotor behaviors

Author

Crittenden, Jill R., primary, Zhai, Shenyu, additional, Sauvage, Magdalena, additional, Kitsukawa, Takashi, additional, Burguière, Eric, additional, Thomsen, Morgane, additional, Zhang, Hui, additional, Costa, Cinzia, additional, Martella, Giuseppina, additional, Ghiglieri, Veronica, additional, Picconi, Barbara, additional, Pescatore, Karen A., additional, Unterwald, Ellen M., additional, Jackson, Walker S., additional, Housman, David E., additional, Caine, S. Barak, additional, Sulzer, David, additional, Calabresi, Paolo, additional, Smith, Anne C., additional, Surmeier, D. James, additional, and Graybiel, Ann M., additional

Published
2021
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15. Striatal Kir2 K+ channel inhibition mediates the antidyskinetic effects of amantadine.

Author

Weixing Shen, Wenjie Ren, Shenyu Zhai, Ben Yang, Vanoye, Carlos G., Mitra, Ananya, George Jr., Alfred L., Surmeier, D. James, Shen, Weixing, Ren, Wenjie, Zhai, Shenyu, Yang, Ben, and George, Alfred L Jr

Subjects
*POTASSIUM metabolism, *DRUG therapy for Parkinson's disease, *RODENTS, *RESEARCH, *FERRANS & Powers Quality of Life Index, *AMANTADINE, *BASAL ganglia, *BIOLOGICAL transport, *ANTIPARKINSONIAN agents, *ANIMAL experimentation, *RESEARCH methodology, *POTASSIUM, *CELL receptors, *DOPA, *NEUROPLASTICITY, *EVALUATION research, *MEDICAL cooperation, *COMPARATIVE studies, *PARKINSON'S disease, *RESEARCH funding, *TARDIVE dyskinesia, *PARKINSONIAN disorders, *POTASSIUM antagonists, *MICE, *PHARMACODYNAMICS, *CHEMICAL inhibitors
Abstract

Levodopa-induced dyskinesia (LID) poses a significant health care challenge for Parkinson's disease (PD) patients. Amantadine is currently the only drug proven to alleviate LID. Although its efficacy in treating LID is widely assumed to be mediated by blockade of N-methyl-D-aspartate (NMDA) glutamate receptors, our experiments demonstrate that at therapeutically relevant concentrations, amantadine preferentially blocks inward-rectifying K+ channel type 2 (Kir2) channels in striatal spiny projection neurons (SPNs) - not NMDA receptors. In so doing, amantadine enhances dendritic integration of excitatory synaptic potentials in SPNs and enhances - not antagonizes - the induction of long-term potentiation (LTP) at excitatory, axospinous synapses. Taken together, our studies suggest that the alleviation of LID in PD patients is mediated by diminishing the disparity in the excitability of direct- and indirect-pathway SPNs in the on state, rather than by disrupting LTP induction. This insight points to a pharmacological approach that could be used to effectively ameliorate LID and improve the quality of life for PD patients. [ABSTRACT FROM AUTHOR]

Published
2020
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16. Ca 2+ -dependent phosphodiesterase 1 regulates the plasticity of striatal spiny projection neuron glutamatergic synapses.

Author

Zhai S, Otsuka S, Xu J, Clarke VRJ, Tkatch T, Wokosin D, Xie Z, Tanimura A, Agarwal HK, Ellis-Davies GCR, Contractor A, and Surmeier DJ

Abstract

Long-term synaptic plasticity at glutamatergic synapses on striatal spiny projection neurons (SPNs) is central to learning goal-directed behaviors and habits. Although considerable attention has been paid to the mechanisms underlying synaptic strengthening and new learning, little scrutiny has been given to those involved in the attenuation of synaptic strength that attends suppression of a previously learned association. Our studies revealed a novel, non-Hebbian, long-term, postsynaptic depression of glutamatergic SPN synapses induced by interneuronal nitric oxide (NO) signaling (NO-LTD) that was preferentially engaged at quiescent synapses. This form of plasticity was gated by local Ca 2+ influx through CaV1.3 Ca 2+ channels and stimulation of phosphodiesterase 1 (PDE1), which degraded cyclic guanosine monophosphate (cGMP) and blunted NO signaling. Consistent with this model, mice harboring a gain-of-function mutation in the gene coding for the pore-forming subunit of CaV1.3 channels had elevated depolarization-induced dendritic Ca 2+ entry and impaired NO-LTD. Extracellular uncaging of glutamate and intracellular uncaging of cGMP suggested that this Ca 2+ -dependent regulation of PDE1 activity allowed for local regulation of dendritic NO signaling. This inference was supported by simulation of SPN dendritic integration, which revealed that dendritic spikes engaged PDE1 in a branch-specific manner. In a mouse model of Parkinson's disease (PD), NO-LTD was absent not because of a postsynaptic deficit in NO signaling machinery, but rather due to impaired interneuronal NO release. Re-balancing intrastriatal neuromodulatory signaling in the PD model restored NO release and NO-LTD. Taken together, these studies provide novel insights into the mechanisms governing NO-LTD in SPN and its role in psychomotor disorders, like PD.

Published
2024
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