Takagi Shunsuke, Balu Darrick T, Coyle Joseph T
Department of Psychiatry and Behavioral Sciences, Tokyo Medical and Dental University Graduate School, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan; Laboratory for Psychiatric and Molecular Neuroscience, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA.
Department of Psychiatry, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA; Laboratory for Psychiatric and Molecular Neuroscience, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA.
Schizophr Res. 2015 Mar;162(1-3):216-21. doi: 10.1016/j.schres.2014.12.034. Epub 2015 Jan 12.
NMDA receptor (NMDAR) hypofunction is a compelling hypothesis for the pathophysiology of schizophrenia, because in part, NMDAR antagonists cause symptoms in healthy adult subjects that resemble schizophrenia. Therefore, NMDAR antagonists have been used as a method to induce NMDAR hypofunction in animals as a pharmacological model of schizophrenia. Serine racemase-null mutant (SR-/-) mice display constitutive NMDAR hypofunction due to the lack of d-serine. SR-/- mice have deficits in tropomyosin-related kinase receptor (TrkB)/Akt signaling and activity regulated cytoskeletal protein (Arc) expression, which mirror what is observed in schizophrenia. Thus, we analyzed these signaling pathways in MK801 sub-chronically (0.15mg/kg; 5days) treated adult wild-type mice. We found that in contrast to SR-/- mice, the activated states of downstream signaling molecules, but not TrkB, increased in MK801 treated mice. Furthermore, there is an age-dependent change in the behavioral reaction of people to NMDAR antagonists. We therefore administered the same dosing regimen of MK801 to juvenile mice and compared them to juvenile SR-/- mice. Our findings demonstrate that pharmacological NMDAR antagonism has different effects on TrkB/Akt signaling than genetically-induced NMDAR hypofunction. Given the phenotypic disparity between the MK801 model and schizophrenia, our results suggest that SR-/- mice more accurately reflect NMDAR hypofunction in schizophrenia.
N-甲基-D-天冬氨酸受体（NMDAR）功能减退是精神分裂症病理生理学的一个极具说服力的假说，部分原因在于，NMDAR拮抗剂会在健康成年受试者身上引发类似精神分裂症的症状。因此，NMDAR拮抗剂已被用作在动物中诱导NMDAR功能减退的一种方法，作为精神分裂症的药理学模型。丝氨酸消旋酶基因敲除突变体（SR-/-）小鼠由于缺乏D-丝氨酸而表现出持续性NMDAR功能减退。SR-/-小鼠在原肌球蛋白相关激酶受体（TrkB）/蛋白激酶B（Akt）信号传导以及活性调节细胞骨架蛋白（Arc）表达方面存在缺陷，这与在精神分裂症中观察到的情况相似。因此，我们分析了用MK801亚慢性（0.15mg/kg；5天）处理的成年野生型小鼠中的这些信号通路。我们发现，与SR-/-小鼠不同，在MK801处理的小鼠中，下游信号分子（而非TrkB）的激活状态增加。此外，人类对NMDAR拮抗剂的行为反应存在年龄依赖性变化。因此，我们给幼年小鼠施用相同剂量方案的MK801，并将它们与幼年SR-/-小鼠进行比较。我们的研究结果表明，药理学上的NMDAR拮抗作用对TrkB/Akt信号传导的影响与基因诱导的NMDAR功能减退不同。鉴于MK801模型与精神分裂症之间的表型差异，我们的结果表明，SR-/-小鼠更准确地反映了精神分裂症中的NMDAR功能减退。
