CaMKIIα expression in a mouse model of NMDAR hypofunction schizophrenia: Putative roles for IGF-1R and TLR4.
CaMKIIα expression in a mouse model of NMDAR hypofunction schizophrenia: Putative roles for IGF-1R and TLR4.
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DOI：
10.1016/j.brainresbull.2017.11.007
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发表时间：
2018-03
影响因子：
3.8
通讯作者：
Lee CC
中科院分区：
文献类型：
--
作者：
Ogundele OM;Lee CC
精神分裂症（SCZ）是一种神经精神疾病，与社会行为缺陷和其他与海马突触功能障碍相关的阴性症状有关。精神分裂症的突触机制以海马n -甲基- d -天冬氨酸受体（NMDAR）活性丧失（NMDAR功能减退）和树突棘为特征。先前的研究表明，海马突触调节钙钙调蛋白依赖性激酶IIα (CaMKIIα)的基因缺失导致小鼠精神分裂症相关的突触和行为缺陷。虽然CaMKIIα参与NMDAR活性的调节，但它同样与神经元中的炎症和促神经激素信号传导有关。基于这些假设，我们推测与CaMKIIα的嗜神经和炎症信号活动相关的非神经递质上游受体可能会改变其突触功能。此外，这些受体（即炎症和嗜神经受体）如何改变CaMKIIα功能（磷酸化）相对于精神分裂症海马NMDAR活性尚不清楚。在这里，我们通过NMDAR抑制诱导精神分裂症后，研究了行为缺陷型精神分裂症小鼠海马中toll样受体（TLR4；炎性）、胰岛素样生长因子受体1 （IGF-1R；嗜神经型）和CaMKIIα表达之间的关系。WT （C57BL/6）小鼠通过腹腔注射30mg/Kg氯胺酮（NMDAR拮抗剂）5天诱导精神分裂症（WT/SCZ）。在最后一次氯胺酮治疗5天后，野生型精神分裂症小鼠在社交能力和社交新奇行为方面表现出缺陷。此外，通过免疫印迹和共聚焦免疫荧光显微镜检测，海马CaMKIIα (p<0.001)和IGF-1R （p<0.001）表达显著降低。此外，WT型精神分裂症小鼠海马区CaMKIIα磷酸化比例增加，TLR4信号（TLR4、NF-κB和MAPK/ErK）上调。为了确定TLR4、IGF-1R和CaMKIIα与精神分裂症患者NMDAR功能障碍之间的功能联系，我们使用aav驱动的Cre-lox技术（TLR4 KD）创建了海马特异性TLR4敲低小鼠。随后，我们在TLR4 KD小鼠中抑制NMDAR功能，试图诱导精神分裂症（TLR4 KD SCZ）。有趣的是，在NMDAR功能减弱后，TLR4 KD海马中IGF-1R和CaMKIIα的表达得以保留。此外，与对照组相比，TLR4 KD SCZ小鼠在社交性和社交新颖性行为方面没有明显缺陷。我们的研究结果表明，在NMDAR功能低下的精神分裂症中，持续的IGF-1R表达可能保持CaMKIIα的突触活性，而TLR4信号通路则会减弱海马CaMKIIα的表达。总之，我们推断IGF-1R缺失和TLR4信号的增加是非神经递质促精神分裂症的线索，可以降低精神分裂症小鼠药理学模型中的突触CaMKIIα活性。
Schizophrenia (SCZ) is a neuropsychiatric disorder that is linked to social behavioral deficits and other negative symptoms associated with hippocampal synaptic dysfunction. Synaptic mechanism of schizophrenia is characterized by loss of hippocampal N-Methyl-D-Aspartate Receptor (NMDAR) activity (NMDAR hypofunction) and dendritic spines. Previous studies show that genetic deletion of hippocampal synaptic regulatory calcium-calmodulin dependent kinase II alpha (CaMKIIα) cause synaptic and behavioral defects associated with schizophrenia in mice. Although CaMKIIα is involved in modulation of NMDAR activity, it is equally linked to inflammatory and neurotropin signaling in neurons. Based on these propositions, we speculate that non-neurotransmitter upstream receptors associated with neurotropic and inflammatory signaling activities of CaMKIIα may alter its synaptic function. Besides, how these receptors (i.e. inflammatory and neurotropic receptors) alter CaMKIIα function (phosphorylation) relative to hippocampal NMDAR activity in schizophrenia is poorly understood. Here, we examined the relationship between toll-like receptor (TLR4; inflammatory), insulin-like growth factor receptor 1 (IGF-1R; neurotropic) and CaMKIIα expression in the hippocampus of behaviorally deficient schizophrenic mice after we induced schizophrenia through NMDAR inhibition. Schizophrenia was induced in WT (C57BL/6) mice through intraperitoneal administration of 30mg/Kg ketamine (NMDAR antagonist) for 5 days (WT/SCZ). Five days after the last ketamine treatment, wild type schizophrenic mice show deficiencies in sociability and social novelty behavior. Furthermore, there was a significant decrease in hippocampal CaMKIIα (p<0.001) and IGF-1R (p<0.001) expression when assessed through immunoblotting and confocal immunofluorescence microscopy. Additionally, WT schizophrenic mice show an increased percentage of phosphorylated CaMKIIα in addition to upregulated TLR4 signaling (TLR4, NF-κB, and MAPK/ErK) in the hippocampus. To ascertain the functional link between TLR4, IGF-1R and CaMKIIα relative to NMDAR hypofunction in schizophrenia, we created hippocampal-specific TLR4 knockdown mouse using AAV-driven Cre-lox technique (TLR4 KD). Subsequently, we inhibited NMDAR function in TLR4 KD mice in an attempt to induce schizophrenia (TLR4 KD SCZ). Interestingly, IGF-1R and CaMKIIα expressions were preserved in the TLR4 KD hippocampus after attenuation of NMDAR function. Furthermore, TLR4 KD SCZ mice showed no prominent defects in sociability and social novelty behavior when compared with the control (WT). Our results show that a sustained IGF-1R expression may preserve the synaptic activity of CaMKIIα while TLR4 signaling ablates hippocampal CaMKIIα expression in NMDAR hypofunction schizophrenia. Together, we infer that IGF-1R depletion and increased TLR4 signaling are non-neurotransmitter pro-schizophrenic cues that can reduce synaptic CaMKIIα activity in a pharmacologic mouse model of schizophrenia.
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