title: Regional specificity of synaptic plasticity deficits in a knock-in mouse model of DYT1 dystonia.
abstract: DYT1 dystonia is a movement disorder caused by a deletion in the C-terminal of the protein torsinA. It is unclear how torsinA mutation might disrupt cellular processes encoding motor activity, and whether this impairment occurs in specific brain regions. Here, we report a selective impairment of corticostriatal synaptic plasticity in knock-in mice heterozygous for Δ-torsinA (Tor1a(+/Δgag) mice) as compared to controls (Tor1a(+/+) mice). In striatal spiny neurons from Tor1a(+/Δgag) mice, high-frequency stimulation failed to induce long-term depression (LTD), whereas long-term potentiation (LTP) exhibited increased amplitude. Of interest, blockade of D2 dopamine receptors (D2Rs) increased LTP in Tor1a(+/+) mice to a level comparable to that measured in Tor1a(+/Δgag) mice and normalized the levels of potentiation across mouse groups. A low-frequency stimulation (LFS) protocol was unable to depotentiate corticostriatal synapses in Tor1a(+/Δgag) mice. Muscarinic M1 acetylcholine receptor (mAChR) blockade rescued plasticity deficits. Additionally, we found an abnormal responsiveness of cholinergic interneurons to D2R activation, consisting in an excitatory response rather than the expected inhibition, further confirming an imbalance between dopaminergic and cholinergic signaling in the striatum. Conversely, synaptic activity and plasticity in the CA1 hippocampal region were unaltered in Tor1a(+/Δgag) mice. Importantly, the M1 mAChR-dependent enhancement of hippocampal LTP was unaffected in both genotypes. Similarly, both basic properties of dopaminergic nigral neurons and their responses to D2R activation were normal. These results provide evidence for a regional specificity of the electrophysiological abnormalities observed and demonstrate the reproducibility of such alterations in distinct models of DYT1 dystonia.
authors: Department of System Medicine, University of Rome "Tor Vergata", Italy; Laboratory of Neurophysiology and Synaptic Plasticity, IRCCS Fondazione Santa Lucia, Rome, Italy.
authors: G
authors: G
authors: Martella
authors: Department of System Medicine, University of Rome "Tor Vergata", Italy.
authors: M
authors: M
authors: Maltese
authors: Laboratory of Neurophysiology and Synaptic Plasticity, IRCCS Fondazione Santa Lucia, Rome, Italy; Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Italy.
authors: R
authors: R
authors: Nisticò
authors: Department of System Medicine, University of Rome "Tor Vergata", Italy.
authors: T
authors: T
authors: Schirinzi
authors: Department of System Medicine, University of Rome "Tor Vergata", Italy.
authors: G
authors: G
authors: Madeo
authors: Department of System Medicine, University of Rome "Tor Vergata", Italy; Laboratory of Neurophysiology and Synaptic Plasticity, IRCCS Fondazione Santa Lucia, Rome, Italy.
authors: G
authors: G
authors: Sciamanna
authors: Department of System Medicine, University of Rome "Tor Vergata", Italy; Laboratory of Neurophysiology and Synaptic Plasticity, IRCCS Fondazione Santa Lucia, Rome, Italy.
authors: G
authors: G
authors: Ponterio
authors: Laboratory of Neurophysiology and Synaptic Plasticity, IRCCS Fondazione Santa Lucia, Rome, Italy.
authors: A
authors: A
authors: Tassone
authors: Department of System Medicine, University of Rome "Tor Vergata", Italy; Laboratory of Neurophysiology and Synaptic Plasticity, IRCCS Fondazione Santa Lucia, Rome, Italy.
authors: G
authors: G
authors: Mandolesi
authors: Laboratory of Neurophysiology and Synaptic Plasticity, IRCCS Fondazione Santa Lucia, Rome, Italy.
authors: V
authors: V
authors: Vanni
authors: Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Italy.
authors: M
authors: M
authors: Pignatelli
authors: Laboratory of Neurophysiology and Synaptic Plasticity, IRCCS Fondazione Santa Lucia, Rome, Italy.
authors: P
authors: P
authors: Bonsi
authors: Department of System Medicine, University of Rome "Tor Vergata", Italy; Laboratory of Neurophysiology and Synaptic Plasticity, IRCCS Fondazione Santa Lucia, Rome, Italy. Electronic address: pisani@uniroma2.it.
authors: A
authors: A
authors: Pisani
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004421:Dystonia / Q000235:genetics* / Q000473:pathology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D018756:GABA Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000235:genetics; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics*; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D009473:Neuronal Plasticity / Q000235:genetics*; D009474:Neurons / Q000502:physiology; D010852:Picrotoxin / Q000494:pharmacology; D010890:Pirenzepine / Q000494:pharmacology; D013569:Synapses / Q000235:genetics / Q000473:pathology*
chemical_list: D004298:Dopamine; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D018832:Molecular Chaperones; D018727:Muscarinic Antagonists; D010852:Picrotoxin; D010890:Pirenzepine; C108175:TOR1A protein, human
keywords: Cholinergic interneurons; D2 dopamine receptor; Dystonia; Long-term depression; Long-term potentiation; Muscarinic receptor antagonists; Striatum