Neuropsychopharmacology Research Unit, Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA.
Int J Neuropsychopharmacol. 2013 May;16(4):905-12. doi: 10.1017/S1461145712000892. Epub 2012 Sep 4.
Parkinson's disease is usually characterized as a movement disorder; however, cognitive abilities that are dependent on the prefrontal cortex decline at an early stage of the disease in most patients. The changes that underlie cognitive deficits in Parkinson's disease are not well understood. We hypothesize that reduced dopamine signalling in the prefrontal cortex in Parkinson's disease is a harbinger of detrimental synaptic changes in pyramidal neurons in the prefrontal cortex, whose function is necessary for normal cognition. Our previous data showed that monkeys exposed to the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), but not exhibiting overt motor deficits (motor-asymptomatic), displayed cognitive deficits in prefrontal cortex-dependent tasks. The present results demonstrate that motor-asymptomatic MPTP-treated monkeys have a reduced dopamine concentration and a substantially lower number (50%) of asymmetric (excitatory) spine synapses in layer II/III, but not layer V, of the dorsolateral prefrontal cortex, compared to controls. In contrast, neither dopamine concentration nor asymmetric synapse number was altered in the entorhinal cortex of MPTP-treated monkeys. Together, these findings suggest that the number of asymmetric spine synapses on dendrites in the prefrontal cortex is dopamine-dependent and that the loss of synapses may be a morphological substrate of the cognitive deficits induced by a reduction in dopamine neurotransmission in this region.
帕金森病通常表现为运动障碍；然而，在大多数患者中，疾病的早期依赖于前额叶皮层的认知能力就会下降。帕金森病中认知缺陷的基础变化尚不清楚。我们假设，帕金森病患者前额叶皮层中的多巴胺信号减少是前额叶皮层中锥体神经元有害突触变化的先兆，而这些神经元的功能对于正常认知是必需的。我们之前的数据表明，暴露于神经毒素 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）但没有表现出明显运动缺陷（运动无症状）的猴子在前额叶皮层依赖的任务中表现出认知缺陷。目前的结果表明，与对照组相比，运动无症状的 MPTP 处理的猴子在背外侧前额叶皮层的 II/III 层（而非 V 层）中多巴胺浓度降低，且不对称（兴奋性）棘突突触数量显著减少（50%）。相比之下，MPTP 处理的猴子的内嗅皮层中多巴胺浓度或不对称突触数量均未改变。这些发现表明，前额叶皮层树突上不对称棘突突触的数量与多巴胺有关，而突触的丧失可能是该区域多巴胺神经传递减少引起的认知缺陷的形态学基础。
