Siekmeier Peter J, vanMaanen David P
1] Laboratory for Computational Neuroscience, McLean Hospital, Belmont, MA, USA [2] Harvard Medical School, Boston, MA, USA.
Neuropsychopharmacology. 2014 Jun;39(7):1713-21. doi: 10.1038/npp.2014.19. Epub 2014 Jan 28.
Since the original formulation of the dopamine hypothesis, a number of other cellular-level abnormalities--eg, NMDA receptor hypofunction, GABA system dysfunction, neural connectivity disturbances--have been identified in schizophrenia, but the manner in which these potentially interact with hyperdopaminergia to lead to schizophrenic symptomatology remains uncertain. Previously, we created a neuroanatomically detailed, biophysically realistic computational model of hippocampus in the control (unaffected) and schizophrenic conditions, implemented on a 72-processor supercomputer platform. In the current study, we apply the effects of dopamine (DA), dose-dependently, to both models on the basis of an exhaustive review of the neurophysiologic literature on DA's ion channel and synaptic level effects. To index schizophrenic behavior, we use the specific inability of the model to attune to the 40 Hz (gamma band) frequency, a finding that has been well replicated in the clinical electroencephalography (EEG) and magnetoencephalography literature. In trials using 20 'simulated patients', we find that DA applied to the control model produces modest increases in 40 Hz activity, similar to experimental studies. However, in the schizophrenic model, increasing DA induces a decrement in 40 Hz resonance. This modeling work is significant in that it suggests that DA's effects may vary based on the neural substrate on which it acts, and--via simulated EEG recordings-points to the neurophysiologic mechanisms by which this may occur. We also feel that it makes a methodological contribution, as it exhibits a process by which a large amount of neurobiological data can be integrated to run pharmacologically relevant in silico experiments, using a systems biology approach.
自从多巴胺假说最初提出以来，在精神分裂症中还发现了许多其他细胞水平的异常情况，例如N-甲基-D-天冬氨酸（NMDA）受体功能减退、γ-氨基丁酸（GABA）系统功能障碍、神经连接紊乱等，但这些异常与多巴胺能亢进相互作用导致精神分裂症症状的方式仍不明确。此前，我们在一个72处理器的超级计算机平台上创建了一个在对照（未受影响）和精神分裂症状态下具有详细神经解剖结构、生物物理逼真的海马体计算模型。在当前研究中，我们在详尽回顾关于多巴胺对离子通道和突触水平影响的神经生理学文献的基础上，将多巴胺（DA）的剂量依赖性效应应用于这两个模型。为了衡量精神分裂症行为，我们利用模型无法适应40赫兹（γ波段）频率这一特定情况，这一发现已在临床脑电图（EEG）和脑磁图文献中得到充分验证。在使用20名“模拟患者”的试验中，我们发现应用于对照模型的多巴胺使40赫兹活动适度增加，这与实验研究结果相似。然而，在精神分裂症模型中，增加多巴胺会导致40赫兹共振减弱。这项建模工作意义重大，因为它表明多巴胺的作用可能因其作用的神经基质而异，并且——通过模拟脑电图记录——指出了可能发生这种情况的神经生理机制。我们还认为它在方法学上做出了贡献，因为它展示了一种利用系统生物学方法整合大量神经生物学数据以进行药理学相关的计算机模拟实验的过程。
