Department of Psychiatry, University of Pittsburgh, Pennsylvania 15213, USA.
Biol Psychiatry. 2010 Jul 1;68(1):25-32. doi: 10.1016/j.biopsych.2010.02.016. Epub 2010 Apr 10.
Spine density on the basilar dendrites of pyramidal neurons is lower in layer 3, but not in layers 5 and 6, in the dorsolateral prefrontal cortex (DLPFC) of subjects with schizophrenia. The expression of CDC42 (cell division cycle 42), a RhoGTPase that regulates the outgrowth of the actin cytoskeleton and promotes spine formation, is also lower in schizophrenia; however, CDC42 mRNA is lower across layers 3-6, suggesting that other lamina-specific molecular alterations are critical for the spine deficits in the illness. The CDC42 effector proteins 3 and 4 (CDC42EP3, CDC42EP4) are preferentially expressed in DLPFC layers 2 and 3, and CDC42EP3 appears to assemble septin filaments in spine necks. Therefore, alterations in CDC42EP3 could contribute to the lamina-specific spine deficits in schizophrenia.
We measured transcript levels of CDC42, CDC42EP3, CDC42EP4; their interacting proteins (septins [SEPT2, 3, 5, 6, 7, 8, and 11], anillin), and other spine-specific proteins (spinophilin, PSD-95, and synaptopodin) in the DLPFC from 31 subjects with schizophrenia and matched normal comparison subjects.
The expression of CDC42EP3 mRNA was significantly increased by 19.7%, and SEPT7 mRNA was significantly decreased by 6.9% in subjects with schizophrenia. Cortical levels of CDC42EP3 and SEPT7 mRNAs were not altered in monkeys chronically exposed to antipsychotic medications.
Activated CDC42 is thought to disrupt septin filaments transiently in spine necks, allowing the molecular translocations required for synaptic potentiation. Thus, altered CDC42 signaling via CDC42EP3 may perturb synaptic plasticity and contribute to the spine deficits observed in layer 3 pyramidal neurons in schizophrenia.
精神分裂症患者背外侧前额叶皮质（DLPFC）的第 3 层锥体神经元基底树突的脊柱密度较低，但第 5 和 6 层则没有。一种调节肌动蛋白细胞骨架生长并促进脊柱形成的 RhoGTPase CDC42（细胞分裂周期蛋白 42）的表达在精神分裂症中也较低；然而，CDC42mRNA 在 3-6 层中都较低，这表明其他层特异性分子改变对于该疾病中的脊柱缺陷至关重要。CDC42 的效应蛋白 3 和 4（CDC42EP3、CDC42EP4）优先在 DLPFC 的第 2 和 3 层表达，而 CDC42EP3 似乎在脊柱颈部组装着隔蛋白丝。因此，CDC42EP3 的改变可能导致精神分裂症中特定于层的脊柱缺陷。
我们测量了 31 名精神分裂症患者和匹配的正常对照者 DLPFC 中的 CDC42、CDC42EP3、CDC42EP4 的转录水平；它们的相互作用蛋白（隔蛋白[SEPT2、3、5、6、7、8 和 11]、肌球蛋白结合蛋白[anillin]）和其他脊柱特异性蛋白（突触磷蛋白、PSD-95 和突触足蛋白）。
精神分裂症患者的 CDC42EP3mRNA 表达增加了 19.7%，SEPT7mRNA 表达减少了 6.9%。在长期接受抗精神病药物治疗的猴子中，CDC42EP3 和 SEPT7mRNA 的皮质水平没有改变。
激活的 CDC42 被认为会在脊柱颈部短暂破坏隔蛋白丝，从而允许突触增强所需的分子易位。因此，通过 CDC42EP3 改变 CDC42 信号可能会扰乱突触可塑性，并导致精神分裂症中第 3 层锥体神经元中观察到的脊柱缺陷。
