Regional specificity of synaptic plasticity deficits in a knock-in mouse model of DYT1 dystonia

详细信息    查看全文

• 作者：G. Martella^a ; ^b ; ¹ ; M. Maltese^a ; ¹ ; R. Nisticò ; ^b ; ^c ; T. Schirinzi^a ; G. Madeo^a ; G. Sciamanna^a ; ^b ; G. Ponterio^a ; ^b ; A. Tassone^b ; G. Mandolesi^a ; ^b ; V. Vanni^b ; M. Pignatelli^c ; P. Bonsi^b ; A. Pisani^a ; ^b ; ^{pisani@uniroma2.it" class="auth_mail}
• 关键词：Dystonia ; Striatum ; D2 dopamine receptor ; Long-term depression ; Long-term potentiation ; Cholinergic interneurons ; Muscarinic receptor antagonists
• 刊名：Neurobiology of Disease
• 出版年：May, 2014
• 年：2014
• 卷：65
• 期：Complete
• 页码：124-132
• 全文大小：1634 K

文摘

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 螖-torsinA (Tor1a^+/螖gag mice) as compared to controls (Tor1a^+/+ mice). In striatal spiny neurons from Tor1a^+/螖gag 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^+/螖gag mice and normalized the levels of potentiation across mouse groups. A low-frequency stimulation (LFS) protocol was unable to depotentiate corticostriatal synapses in Tor1a^+/螖gag 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^+/螖gag 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.