Authors

Sciamanna, G., Ponterio, G., Tassone, A., Maltese, M., Madeo, G., Martella, G., … Pisani, A.

Affiliations

Department of Systems Medicine, University of Rome Tor Vergata , Italy, Laboratory of Neurophysiology and Synaptic Plasticity, IRCCS Fondazione Santa Lucia, Rome, Italy, ADDEX Therapeutics, Geneva, Switzerland.

Application Area

Electrophysiology

Uncaging

Abstract

Early onset torsion dystonia (DYT1) is an autosomal dominantly inherited disorder caused by deletion in TOR1A gene. Evidence suggests that TOR1A mutation produces dystonia through an aberrant neuronal signalling within the striatum, where D2 dopamine receptors (D2R) produce an abnormal excitatory response in cholinergic interneurons (ChIs) in different models of DYT1 dystonia. The excitability of ChIs may be modulated by group I metabotropic glutamate receptor subtypes (mGlu1 and 5). We performed electrophysiological and calcium imaging recordings from ChIs of both knock-in mice heterozygous for Δ-torsinA (Tor1a(+/Δgag) mice) and transgenic mice overexpressing human torsinA (hMT1). We demonstrate that the novel negative allosteric modulator (NAM) of metabotropic glutamate 5 (mGlu) receptor, dipraglurant (ADX48621) counteracts the abnormal membrane responses and calcium rise induced either by the D2R agonist quinpirole or by caged dopamine (NPEC-Dopamine) in both models. These inhibitory effects were mimicked by two other well-characterized mGlu5 receptor antagonists, SIB1757 and MPEP, but not by mGlu1 antagonism. D2R and mGlu5 post-receptor signalling may converge on PI3K/Akt pathway. Interestingly, we found that the abnormal D2R response was prevented by the selective PI3K inhibitor, LY294002, whereas PLC and PKC inhibitors were both ineffective. Currently, no satisfactory pharmacological treatment is available for DYT1 dystonia patients. Our data show that negative modulation of mGlu5 receptors may counteract abnormal D2R responses, normalizing cholinergic cell excitability, by modulating the PI3K/Akt post-receptor pathway, thereby representing a novel potential treatment of DYT1 dystonia.

Extract

… “applied by means of Polychrome IV monochromator (TILL Photonics, Ger- many),and a pE-2 LED systems(CoolLED,UK).”…

Product Associated Features

pE-2: A repeatable, controllable modular system with 20 different LED peaks. Instant on/off and intensity (0-100%) control.

Diascopic Technique

DIC

Live Cell Issues

-

Product Type

-

Journal

Neuropharmacology

Year of Publication

2014

Country of Publication

Switzerland