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.
J Neurosci. 2012 Aug 29;32(35):11991-2004. doi: 10.1523/JNEUROSCI.0041-12.2012.
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.
丘脑核间层核投射将感觉信号传递到纹状体胆碱能中间神经元。这些神经元以起搏活动暂停作为反应，从而能够与皮质传入到中等棘突神经元（MSNs）进行突触整合，因此在运动功能中发挥着关键作用。在具有 DYT1 扭转痉挛突变的小鼠中，刺激丘脑纹状体轴突，模拟对显著事件的反应，引起短暂的暂停，并在中间神经元中引发异常的尖峰活动。这种改变的模式导致 M1 和 M2 毒蕈碱受体介导的 MSNs 中的突触活动的时间序列发生显著重排，包括突触后电流增加和突触前抑制减少。与乙酰胆碱的主要作用一致，降低胆碱能张力或拮抗突触后 M1 毒蕈碱受体均可使突触活动正常化。我们的数据表明，丘脑纹状体和皮质纹状体传入之间的突触整合存在异常的时间窗口，这可能改变动作选择过程，从而使 DYT1 基因突变携带者易于发生扭转运动。
