Agrawal Rimjhim, Kalmady Sunil Vasu, Venkatasubramanian Ganesan
Translational Psychiatry Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neuro Sciences, Bangalore, India.
Clin Psychopharmacol Neurosci. 2017 May 31;15(2):115-125. doi: 10.9758/cpn.2017.15.2.115.
Deficient brain-derived neurotrophic factor (BDNF) is one of the important mechanisms underlying the neuroplasticity abnormalities in schizophrenia. Aberration in BDNF signaling pathways directly or circuitously influences neurotransmitters like glutamate and gamma-aminobutyric acid (GABA). For the first time, this study attempts to construct and simulate the BDNF-neurotransmitter network in order to assess the effects of BDNF deficiency on glutamate and GABA.
Using CellDesigner, we modeled BDNF interactions with calcium influx via N-methyl-D-aspartate receptor (NMDAR)- Calmodulin activation; synthesis of GABA via cell cycle regulators protein kinase B, glycogen synthase kinase and β-catenin; transportation of glutamate and GABA. Steady state stability, perturbation time-course simulation and sensitivity analysis were performed in COPASI after assigning the kinetic functions, optimizing the unknown parameters using random search and genetic algorithm.
Study observations suggest that increased glutamate in hippocampus, similar to that seen in schizophrenia, could potentially be contributed by indirect pathway originated from BDNF. Deficient BDNF could suppress Glutamate decarboxylase 67-mediated GABA synthesis. Further, deficient BDNF corresponded to impaired transport via vesicular glutamate transporter, thereby further increasing the intracellular glutamate in GABAergic and glutamatergic cells. BDNF also altered calcium dependent neuroplasticity via NMDAR modulation. Sensitivity analysis showed that Calmodulin, cAMP response element-binding protein (CREB) and CREB regulated transcription coactivator-1 played significant role in this network.
The study presents quantitative model of biochemical network constituting the key signaling molecules implicated in schizophrenia pathogenesis. It provides mechanistic insights into putative contribution of deficient BNDF towards alterations in neurotransmitters and neuroplasticity that are consistent with current understanding of the disorder.
脑源性神经营养因子（BDNF）缺乏是精神分裂症神经可塑性异常的重要机制之一。BDNF信号通路的异常直接或间接影响谷氨酸和γ-氨基丁酸（GABA）等神经递质。本研究首次尝试构建并模拟BDNF-神经递质网络，以评估BDNF缺乏对谷氨酸和GABA的影响。
我们使用CellDesigner对BDNF与通过N-甲基-D-天冬氨酸受体（NMDAR）-钙调蛋白激活的钙内流的相互作用、通过细胞周期调节因子蛋白激酶B、糖原合酶激酶和β-连环蛋白合成GABA以及谷氨酸和GABA的转运进行建模。在指定动力学函数后，使用随机搜索和遗传算法优化未知参数，然后在COPASI中进行稳态稳定性、扰动时间进程模拟和敏感性分析。
研究观察结果表明，海马体中谷氨酸增加，类似于精神分裂症患者中所见，可能是由源自BDNF的间接途径导致的。BDNF缺乏可能会抑制谷氨酸脱羧酶67介导的GABA合成。此外，BDNF缺乏对应于通过囊泡谷氨酸转运体的转运受损，从而进一步增加了GABA能和谷氨酸能细胞内的谷氨酸。BDNF还通过NMDAR调节改变钙依赖性神经可塑性。敏感性分析表明，钙调蛋白、cAMP反应元件结合蛋白（CREB）和CREB调节转录共激活因子-1在该网络中起重要作用。
该研究提出了构成精神分裂症发病机制中关键信号分子的生化网络的定量模型。它为BDNF缺乏对神经递质和神经可塑性改变的假定贡献提供了机制性见解，这与目前对该疾病的理解一致。
