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Striatal Kir2 K+ channel inhibition mediates the antidyskinetic effects of amantadine
Weixing Shen, … , Alfred L. George Jr., D. James Surmeier
Weixing Shen, … , Alfred L. George Jr., D. James Surmeier
Published April 20, 2020
Citation Information: J Clin Invest. 2020;130(5):2593-2601. https://doi.org/10.1172/JCI133398.
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Research Article Neuroscience

Striatal Kir2 K+ channel inhibition mediates the antidyskinetic effects of amantadine

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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.

Authors

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

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Figure 2

AMT increased somatic excitability in dSPNs and iSPNs.

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AMT increased somatic excitability in dSPNs and iSPNs.
(A) Current-clamp...
(A) Current-clamp analysis of membrane input resistance (Rin) and time constant (τ) at SPN resting membrane potential. AMT (100 μM) increased both Rin (B) (control n = 19, AMT = 19) and τ (C) (control n = 19, AMT = 19). (D–F) Somatic excitability of SPNs was increased by AMT (100 μM) in both iSPNs and dSPNs. Somatic excitability was assessed by somatic current injection before and after application of 100 μM AMT. (D) AMT reduced rheobase current (control n = 12, AMT = 12). (E) Sample voltage recordings in response to a 100-pA current injection in an iSPN and a 160-pA current injection in a dSPN. (F) Effect of 100 μM AMT on the number of action potentials (APs) evoked by 500-ms current injections (iSPN n = 6, dSPN n = 6). *P < 0.05, ***P < 0.001 by Mann-Whitney test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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