Prevention of dystonia by control of 5HT-2A receptor-dependent excitability in the deep cerebellar nuclei

Abstract

The serotonin (5HT) system especially related to emotional change and locomotion, but the ways in which 5HT affects dystonia syndrome remain unclear. Serotonin modulates the motor output of the cerebellum to enhance muscle tension in this study. Repetitive photostimulation of the 5HT-fDCN circuit gradually increases the excitability of the fDCN neurons, leading to dystonia in wild type mice. Activation of the 5HT-fDCN inputs facilitates Ca$^{2+}$ in the fDCN neurons, as well as up-regulation of GluA1 and down-regulation of GluA2 AMPA receptor subunits. By expressing OptoSTIM1 in the fDCN neurons, light-induced increases in Ca$^{2+}$ signaling can recapitulate dystonia. On the pharmacological side, injection of 5HT2A receptor antagonist and photoinhibition of the 5HT inputs to the fastigial deep cerebellar nuclei (fDCN) prevent dystonia in cacna1a$^{tg/tg}$ mice. The Ca$^{2+}$ signals increase accompanied by dystonic behavior, whereas a decrease in Ca$^{2+}$ signals with dystonia by 5HT2A receptor antagonist in this study. These results suggest 5HT-dependent neuronal excitability mediates increases in muscle tension and suggest ways to improve life for patients suffering from motor dysfunctions.