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

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 3

Blocking Kir2 current enhanced dendritic excitability in SPNs.

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Blocking Kir2 current enhanced dendritic excitability in SPNs. (A) Schem...
(A) Schematic depicting the calcium imaging assay. (B) Sample bAP-evoked Ca2+ transients (top) before (black) and after application of 100 μM AMT (red). The current injection (middle) and voltage recordings (bottom) are also shown in temporal registration. (C and D) Box plots showing the effect of AMT on bAP-evoked Ca2+ transients in proximal (C) and distal (D) dendrites. AMT significantly increases Ca2+ transients only in distal dendrites, while it slows calcium transient decay in both proximal and distal dendrites (n = 16 dendrites from 8 cells). (E–G) AMT (100 μM) enhances distal uncaging-evoked synaptic response. (E) Low (top) and high (bottom) magnification maximum-intensity projections of an iSPN filled with Alexa Fluor 568. A single spine (indicated with a yellow circle) was stimulated with 1-ms uncaging laser pulses. (F) Sample somatic voltage recordings in response to glutamate uncaging. (G) Box plot showing the effect of AMT (100 μM) (n = 12 spines from 7 cells). NS, not significant. (H–K) EPSP trains were evoked by local stimulation of glutamatergic afferent fibers at 50 Hz. AMPAR-mediated input was isolated by application of antagonists. (H and I) At resting membrane potentials (approximately –90 mV), EPSPs summed sublinearly with the EPSP5/EPSP1 ratio between 1 and 2. AMT (100 μM) increased EPSP summation in iSPNs. The EPSP5/EPSP1 ratio increased in the presence of AMT (control n =6, AMT n = 6). (J and K) EPSPs before (black) and after (red) AMT application in which Vm was held constant at –70 mV. AMT (100 μM) significantly increased the half-width of the second EPSPs (control n = 5, AMT n = 5). *P < 0.05; ***P < 0.001 by Wilcoxon’s test (C, D, and G) or Mann-Whitney test (I and K).