Inhibition of the tyrosine phosphatase STEP61 restores BDNF expression and reverses motor and cognitive deficits in phencyclidine-treated mice.
Inhibition of the tyrosine phosphatase STEP61 restores BDNF expression and reverses motor and cognitive deficits in phencyclidine-treated mice.
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抑制酪氨酸磷酸酶Step61可恢复BDNF的表达，并逆转苯基二酮治疗小鼠的运动和认知缺陷。
DOI：
10.1007/s00018-015-2057-1
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发表时间：
2016-04
期刊：
影响因子：
--
通讯作者：
Lombroso PJ
中科院分区：
文献类型：
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作者：
Xu J;Kurup P;Baguley TD;Foscue E;Ellman JA;Nairn AC;Lombroso PJ
脑源性神经营养因子（BDNF）和富含酪氨酸的蛋白酪氨酸磷酸酶61（STEP 61）在脑中具有相反的功能，BDNF支持突触强化，而STEP 61反对突触强化。BDNF和STEP 61在许多脑疾病中也表现出相反的表达模式，包括精神分裂症（SZ）。NMDAR拮抗剂如苯环己哌啶（PCP）在啮齿动物模型和未受影响的个体中引起SZ样症状，并加剧SZ中的精神病发作。在这里，我们的特点是调节BDNF的表达STEP 61，利用PCP处理的皮质培养和PCP处理的小鼠。PCP处理的皮质神经元表现出STEP 61水平的增加和BDNF表达的减少。通过STEP 61敲低或使用STEP抑制剂TC-2153来防止BDNF表达的减少。PCP诱导的STEP 61表达的增加与CREB依赖性BDNF转录的抑制有关。同样，STEP的遗传和药理学抑制防止PCP诱导的BDNF表达在体内的减少和正常化PCP诱导的过度运动和认知缺陷。这些结果表明，STEP 61调节BDNF表达的机制，与CNS疾病的认知功能的影响。
Brain-derived neurotrophic factor (BDNF) and STriatal-Enriched protein tyrosine Phosphatase 61 (STEP61) have opposing functions in the brain, with BDNF supporting and STEP61 opposing synaptic strengthening. BDNF and STEP61 also exhibit an inverse pattern of expression in a number of brain disorders, including schizophrenia (SZ). NMDAR antagonists such as phencyclidine (PCP) elicit SZ-like symptoms in rodent models and unaffected individuals, and exacerbate psychotic episodes in SZ. Here we characterize the regulation of BDNF expression by STEP61, utilizing PCP-treated cortical culture and PCP-treated mice. PCP-treated cortical neurons showed both an increase in STEP61 levels and a decrease in BDNF expression. The reduction in BDNF expression was prevented by STEP61 knockdown or use of the STEP inhibitor, TC-2153. The PCP-induced increase in STEP61 expression was associated with the inhibition of CREB-dependent BDNF transcription. Similarly, both genetic and pharmacologic inhibition of STEP prevented the PCP-induced reduction in BDNF expression in vivo and normalized PCP-induced hyperlocomotion and cognitive deficits. These results suggest a mechanism by which STEP61 regulates BDNF expression, with implications for cognitive functioning in CNS disorders.