Editors' ChoiceParkinson’s Disease

Better treatment for dyskinesia

Sci. Signal.  24 Nov 2015:
Vol. 8, Issue 404, pp. ec344
DOI: 10.1126/scisignal.aad9141

Goal-directed movement is primarily controlled through a neuronal circuit in the striatum that includes direct-pathway spiny neurons (dSPNs) and requires balanced cholinergic and dopaminergic input. Loss of the dopaminergic neurons in this circuit results in Parkinson’s disease, which is treated by administering the dopamine precursor ʟ-DOPA to enhance dopamine release from the remaining neurons. Unfortunately, ʟ-DOPA treatment itself produces dyskinetic movement. Shen et al. tested the hypotheses (i) that signaling through muscarinic acetylcholine type 4 receptors (M4Rs) in direct-pathway spiny neurons (dSPNs) suppressed a specific form of long-term potentiation (LTP) and promoted long-term depression (LTD) and (ii) that pharmacologically enhancing M4R activity would reduce ʟ-DOPA–induced dyskinesia (LID) in rodent and primate models of Parkinson’s disease. dSPNs receive dopaminergic, cholinergic, and glutamatergic input. Using transgenic mice that enabled the precise identification of dSPNs, electrophysiological experiments showed that pharmacological inhibition of dopamine type 1 receptors (D1Rs) enabled LTD in dSPNs and that coapplication of an M4R antagonist blocked LTD. Even without inhibiting D1Rs, LTD occurred in response to a longer train of repetitive stimulations in the presence of an M4R allosteric agonist, which enhances the response to endogenous released acetylcholine but does not directly stimulate the receptors. Thus, enhanced M4R signaling could overcome D1R signaling in dSPNs. Repeating the experiments with mice engineered to lack M4R in dSPNs confirmed that the receptor functioned postsynaptically to promote LTD. The M4R allosteric agonist decreased calcium signals induced by uncaging glutamate at dendritic spines of dSPNs and exposed to a D1R agonist (to mimic simultaneous glutamatergic and dopaminergic input). Electrophysiological studies showed that M4R activity impaired LTP induction and reversed LTP through a process called depotentiation. Collectively, these data showed that enhancing M4R activity opposed dopaminergic signaling through D1R and thus reduced dSPN activity. In a mouse model of LID, application of the M4R allosteric agonist to slice preparations restored synaptic plasticity in dSPNs to that of the control by reducing LTP induction and enabling depotentiation. Administration of M4R allosteric agonists to either mouse or nonhuman primate models of Parkinson’s disease reduced dyskinetic movements induced by ʟ-DOPA, suggesting that enhancing the M4R pathway may be a therapeutic strategy to reduce the negative effects of ʟ-DOPA treatment.

W. Shen, J. L. Plotkin, V. Francardo, W. K. D. Ko, Z. Xie, Q. Li, T. Fieblinger, J. Wess, R. R. Neubig, C. W. Lindsley, P. J. Conn, P. Greengard, E. Bezard, M. A. Cenci, D. J. Surmeier, M4 muscarinic receptor signaling ameliorates striatal plasticity deficits in models of L-DOPA-induced dyskinesia. Neuron 88, 762–773 (2015). [PubMed]

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