title: Cholinergic dysfunction alters synaptic integration between thalamostriatal and corticostriatal inputs in DYT1 dystonia.
abstract: Projections from thalamic intralaminar nuclei convey sensory signals to striatal cholinergic interneurons. These neurons respond with a pause in their pacemaking activity, enabling synaptic integration with cortical inputs to medium spiny neurons (MSNs), thus playing a crucial role in motor function. In mice with the DYT1 dystonia mutation, stimulation of thalamostriatal axons, mimicking a response to salient events, evoked a shortened pause and triggered an abnormal spiking activity in interneurons. This altered pattern caused a significant rearrangement of the temporal sequence of synaptic activity mediated by M(1) and M(2) muscarinic receptors in MSNs, consisting of an increase in postsynaptic currents and a decrease of presynaptic inhibition, respectively. Consistent with a major role of acetylcholine, either lowering cholinergic tone or antagonizing postsynaptic M(1) muscarinic receptors normalized synaptic activity. Our data demonstrate an abnormal time window for synaptic integration between thalamostriatal and corticostriatal inputs, which might alter the action selection process, thereby predisposing DYT1 gene mutation carriers to develop dystonic movements.
authors.affiliation: Department of Neuroscience, University Tor Vergata/Laboratory of Neurophysiology and Synaptic Plasticity, Fondazione Santa Lucia Istituto di Ricovero e Cura a Carattere Scientifico, 00143 Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Sciamanna
authors.forename: Annalisa
authors.initials: A
authors.lastname: Tassone
authors.forename: Georgia
authors.initials: G
authors.lastname: Mandolesi
authors.forename: Francesca
authors.initials: F
authors.lastname: Puglisi
authors.forename: Giulia
authors.initials: G
authors.lastname: Ponterio
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Martella
authors.forename: Graziella
authors.initials: G
authors.lastname: Madeo
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bernardi
authors.forename: David G
authors.initials: DG
authors.lastname: Standaert
authors.forename: Paola
authors.initials: P
authors.lastname: Bonsi
authors.forename: Antonio
authors.initials: A
authors.lastname: Pisani
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D059329:Cholinergic Neurons / Q000473:pathology*; D003342:Corpus Striatum / Q000502:physiology*; D004421:Dystonia / Q000235:genetics* / Q000503:physiopathology; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009434:Neural Pathways / Q000473:pathology; D013569:Synapses / Q000473:pathology*; D013788:Thalamus / Q000502:physiology*; D013997:Time Factors
chemical_list: C491548:Dyt1 protein, mouse; D018832:Molecular Chaperones