Striatal Kir2 K+ channel inhibition mediates the antidyskinetic effects of amantadine
Weixing Shen, Wenjie Ren, Shenyu Zhai, Ben Yang, Carlos G. Vanoye, Ananya Mitra, Alfred L. George Jr., D. James Surmeier
Weixing Shen, Wenjie Ren, Shenyu Zhai, Ben Yang, Carlos G. Vanoye, Ananya Mitra, Alfred L. George Jr., D. James Surmeier
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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 4

AMT promoted LTP induction.

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AMT promoted LTP induction. (A) Schematic illustrating the LTD induction...
(A) Schematic illustrating the LTD induction protocol. (B) LTD was induced by a pre-post timing pairing in iSPNs. Plots show EPSP amplitude (amp) and input resistance (Ri) as a function of time. Scale bars: 3 mV × 50 ms. (C) In the presence of AMT (100 μM), the post-pre timing pairing revealed LTP. Scale bars: 4 mV × 60 ms. (D) In control, post-pre pairing revealed LTD in iSPNs, whereas in AMT, the same protocol promoted LTP (control n = 4, AMT n = 5, P < 0.05 by Mann-Whitney test). Data are represented as mean ± SEM. (E) The post-pre pairing induced LTD. Scale bars: 4 mV × 50 ms. (F) In contrast, AMT (100 μM) promoted induction of iSPN LTP in the dyskinetic state. Scale bars: 5 mV × 60 ms. (G) Plot of the average EPSP amplitudes as a function of time. Data are shown as mean ± SEM. Control n = 6, AMT n = 7, P < 0.05 by Mann-Whitney test. (H) Schematic depicting the LTP induction protocol. (I) LTP was induced by a pre-post pairing in dSPNs. Scale bars: 5 mV × 60 ms. (J) In the presence of AMT (100 μM), the pre-post pairing led to LTP. Scale bars: 4 mV × 60 ms. In both naive (K) and dyskinetic (L) animals, pre-post pairing induced dSPN LTP. Bath application of AMT (100 μM) did not alter LTP induction in either naive or LID tissue (naive: control n = 5, AMT n = 6, P > 0.05 by Mann-Whitney test. Dyskinetic: control n = 5, AMT n = 6, P > 0.05 by Mann-Whitney test). (M) Sample voltage recordings. (N and O) Effect of 100 μM AMT on the number of APs (iSPN n = 9, dSPN n = 6) in the dyskinetic state.