Neuropsycopharmacology Laboratory, Mayo Clinic, Jacksonville, Florida, USA.
PLoS One. 2013 May 14;8(5):e52147. doi: 10.1371/journal.pone.0052147. Print 2013.
Mitochondrial short and long-range movements are necessary to generate the energy needed for synaptic signaling and plasticity. Therefore, an effective mechanism to transport and anchor mitochondria to pre- and post-synaptic terminals is as important as functional mitochondria in neuronal firing. Mitochondrial movement range is regulated by phosphorylation of cytoskeletal and motor proteins in addition to changes in mitochondrial membrane potential. Movement direction is regulated by serotonin and dopamine levels. However, data on mitochondrial movement defects and their involvement in defective signaling and neuroplasticity in relationship with mood disorders is scarce. We have previously reported the effects of lithium, valproate and a new antipsychotic, paliperidone on protein expression levels at the synaptic level.
Mitochondrial function defects have recently been implicated in schizophrenia and bipolar disorder. We postulate that mood stabilizer treatment has a profound effect on mitochondrial function, synaptic plasticity, mitochondrial migration and direction of movement.
Synaptoneurosomal preparations from rat pre-frontal cortex were obtained after 28 daily intraperitoneal injections of lithium, valproate and paliperidone. Phosphorylated proteins were identified using 2D-DIGE and nano LC-ESI tandem mass spectrometry.
Lithium, valproate and paliperidone had a substantial and common effect on the phosphorylation state of specific actin, tubulin and myosin isoforms as well as other proteins associated with neurofilaments. Furthermore, different subunits from complex III and V of the electron transfer chain were heavily phosphorylated by treatment with these drugs indicating selective phosphorylation.
Mood stabilizers have an effect on mitochondrial function, mitochondrial movement and the direction of this movement. The implications of these findings will contribute to novel insights regarding clinical treatment and the mode of action of these drugs.
线粒体的短距离和长距离运动对于产生突触信号和可塑性所需的能量是必要的。因此，将线粒体运输和锚定到突触前和突触后末端的有效机制与神经元放电中的功能性线粒体一样重要。除了线粒体膜电位的变化外，细胞骨架和运动蛋白的磷酸化也调节线粒体的运动范围。运动方向受血清素和多巴胺水平的调节。然而，关于线粒体运动缺陷及其与情绪障碍相关的信号转导和神经可塑性缺陷的关系的数据很少。我们之前已经报道了锂、丙戊酸和一种新型抗精神病药帕利哌酮对突触水平蛋白表达水平的影响。
线粒体功能缺陷最近与精神分裂症和双相情感障碍有关。我们假设心境稳定剂治疗对线粒体功能、突触可塑性、线粒体迁移和运动方向有深远的影响。
通过对大鼠前额叶皮质进行 28 天腹腔内注射锂、丙戊酸和帕利哌酮，获得突触神经小体制剂。使用 2D-DIGE 和纳升 LC-ESI 串联质谱法鉴定磷酸化蛋白。
锂、丙戊酸和帕利哌酮对特定肌动蛋白、微管蛋白和肌球蛋白同工型以及与神经丝相关的其他蛋白质的磷酸化状态有显著的共同影响。此外，这些药物处理后，电子传递链复合物 III 和 V 的不同亚基也被强烈磷酸化，表明存在选择性磷酸化。
心境稳定剂对线粒体功能、线粒体运动及其运动方向有影响。这些发现的意义将有助于对这些药物的临床治疗和作用模式有新的认识。
