Intellectual Developmental Disabilities Research Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
J Neurosci Res. 2010 Jun;88(8):1764-76. doi: 10.1002/jnr.22327.
alpha-Synuclein (alpha-Syn) is a presynaptic protein implicated in Parkinson's disease (PD). Mice overexpressing human wildtype (WT) alpha-Syn under the Thy1 promoter show high levels of alpha-Syn in cortical and subcortical regions, exhibit progressive sensorimotor anomalies, as well as non-motor abnormalities and are considered models of pre-manifest PD as there is little evidence of early loss of dopaminergic (DA) neurons. We used whole-cell patch clamp recordings from visually identified striatal medium-sized spiny neurons (MSSNs) in slices from alpha-Syn and WT littermate control mice at 35, 90 and 300 days of age to examine corticostriatal synaptic function. MSSNs displayed significant decreases in the frequency of spontaneous excitatory postsynaptic currents (EPSCs) in alpha-Syn mice at all ages. This difference persisted in the presence of tetrodotoxin, indicating it was independent of action potentials. Stimulation thresholds for evoking EPSCs were significantly higher and responses were smaller in alpha-Syn mice. These data suggest a decrease in neurotransmitter release at the corticostriatal synapse. At 90 days the frequency of spontaneous GABA(A) receptor-mediated synaptic currents was decreased in MSSNs but increased in cortical pyramidal neurons. These observations indicate that high levels of expression of alpha-Syn alter corticostriatal synaptic function early and they provide evidence for early synaptic dysfunction in a pre-manifest model of PD. Of importance, these changes are opposite to those found in DA-depletion models, suggesting that before degeneration of DA neurons in the substantia nigra synaptic adaptations occur at the corticostriatal synapse that may initiate subtle preclinical manifestations.
α-突触核蛋白（α-Syn）是一种与帕金森病（PD）相关的突触前蛋白。在 Thy1 启动子的控制下，过表达人野生型（WT）α-Syn 的小鼠在皮质和皮质下区域表现出高水平的α-Syn，表现出进行性感觉运动异常，以及非运动异常，被认为是前驱 PD 的模型，因为几乎没有早期多巴胺能（DA）神经元丢失的证据。我们使用全细胞膜片钳记录技术，从 35、90 和 300 天大的α-Syn 和 WT 同窝对照小鼠的脑片上视觉鉴定的纹状体中型棘突神经元（MSSNs）中进行记录，以检查皮质纹状体突触功能。在所有年龄段的α-Syn 小鼠中，MSSNs 自发兴奋性突触后电流（EPSCs）的频率均显著降低。在使用河豚毒素的情况下，这种差异仍然存在，表明它与动作电位无关。诱发 EPSCs 的刺激阈值在α-Syn 小鼠中明显升高，反应幅度减小。这些数据表明皮质纹状体突触的神经递质释放减少。在 90 天时，MSSNs 中自发性 GABA(A) 受体介导的突触电流的频率降低，但皮质锥体神经元中增加。这些观察结果表明，α-Syn 的高表达水平早期改变了皮质纹状体突触功能，并为前驱 PD 模型中的早期突触功能障碍提供了证据。重要的是，这些变化与 DA 耗竭模型中的变化相反，表明在黑质中 DA 神经元变性之前，皮质纹状体突触发生了适应性变化，可能引发了微妙的临床前表现。
