水通道蛋白4对成年CD1小鼠脑内神经再生的调节作用
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摘要
水通道蛋白(aquaporins,AQPs)是一组广泛存在于动植物细胞膜上与水转运相关的整合蛋白,参与水分子的跨膜转运和细胞内外环境稳态的调节。迄今为止,在哺乳动物组织中已鉴定出13种水通道蛋白(AQP0-AQP12)。其中,AQP4是成年动物脑内表达量最丰富、水通透效率最高的水通道亚型,主要分布于星形胶质细胞、室管膜细胞以及成体神经干细胞(adult neural stem cell,ANSCs)。AQP4对水分子具有双向通透的特性,使其能够在生理及病理状态下快速调节细胞内外水分子的重分布。在细胞毒性脑水肿中,AQP4可促进水分子进入星形胶质细胞,加剧脑水肿;在血管源性脑水肿中,AQP4可加速水肿液从脑实质向脑脊液与血管的外排,减轻脑水肿。星形胶质细胞是脑内数量最多的细胞,参与细胞外离子缓冲、神经递质传导、生长因子释放以及神经免疫调节。应用AQP4基因敲除鼠的研究显示,AQP4不仅是脑内一种特异性的水转运孔道,而且调控星形胶质细胞功能,并广泛参与脑内微环境稳态的维持、神经传导等重要脑生理功能的调节。
成年神经再生(adult neurogenesis)是当今神经科学研究中最活跃、进展最快的领域之一。成年动物脑中侧脑室下区(subventricular zone,SVZ)与海马齿状回颗粒细胞下区(subgranular zone,SGZ)存在ANSCs,参与脑中持续的神经再生过程。ANSCs能自我更新、持续增殖并分化成神经元、星形胶质细胞和少突胶质细胞。生理状态下,神经再生参与学习记忆、择偶行为等多种脑高级功能的形成。在病理情况下,神经再生能力的改变参与多种神经精神疾病的发生及神经修复过程。例如,抑郁症患者SGZ神经再生减弱,抗抑郁药物可通过增强SGZ神经再生产生治疗学效应;增强脑卒中后神经再生能显著改善认知与运动功能缺损。但是,目前对于调节成年神经再生过程的分子机制认识非常有限。因此,探索成年神经再生的调节机制将为发展靶向于调制神经再生的药物提供新思路,为神经干细胞移植治疗积累学术基础。
近年来的研究发现,AQP4高度表达于SVZ、SGZ等神经再生显著的脑区,并且在鼠、猪及人类神经干细胞和神经祖细胞均有AQP4的表达。然而,AQP4是否参与调节成年神经再生?目前尚未见报道。因此,本文第一部分工作首先应用自行制备的AQP4基因敲除鼠在体研究AQP4基因敲除对SVZ/SGZ神经干细胞增殖及SVZ结构发育的影响;第二部分工作应用离体培养的小鼠SVZ ANSCs,研究AQP4基因敲除对ANSCs自我更新、增殖、迁移、分化等生物学特性的影响及其调节机制;第三部分工作在建立慢性温和应激(chronic mild stress,CMS)抑郁症模型小鼠的基础上,研究AQP4基因敲除对经典抗抑郁药物氟西汀(fluoxetine)促SGZ神经再生作用的影响及其相关的分子机制。研究结果开拓了AQP4神经生物学研究的新领域,深化对AQP4生理及病理功能的认识,揭示AQP4是调制成年神经再生的重要靶点,为研发针对神经修复的治疗药物提供新的靶标。
第一部分AQP4基因敲除对成年CD1小鼠SVZ/SGZ神经干细胞增殖及SVZ结构发育的影响
目的:研究、阐明AQP4在成年小鼠SVZ/SGZ神经干细胞增殖及SVZ结构发育中的作用。
方法:应用2月龄AQP4野生型(wildtype,AQP4~+/+)及AQP4基因敲除型(AQP4 knockout,AQP4-/-)雄性CD1小鼠,经腹腔给予5-溴-2-脱氧尿嘧啶核苷(5-bromo-2-deoxyuridine,BrdU,50mg/kg,每2小时一次,共4次)24小时后麻醉、灌注固定、取脑、冰冻切片,行BrdU免疫组化。取成年小鼠侧脑室(lateral ventricle,LV)背外侧区组织固定后行锇酸染色,电镜观察SVZ细胞结构。应用出生后1、7、14、28、56日龄AQP4+/+及AQP4-/- CD1小鼠,断头取脑,石蜡包埋后切取侧脑室前脚至中脑导水管出现部位冠状切片,行HE染色及AQP4免疫组化,测定LV容积、计数SVZ细胞密度,分析SVZ AQP4表达的灰度值。取新鲜全脑组织,用干/湿比重法测定脑含水量。取2月龄小鼠,打开小脑延髓池,用滤纸(1 mm×5 mm)称重法测定不同时间点脑脊液量。
结果:1)AQP4基因敲除显著抑制成年小鼠SVZ神经干细胞增殖,对SGZ神经干细胞增殖无显著影响。2)AQP4-/-小鼠侧脑室容积显著减小,室管膜层不连续,部分区域室管膜细胞缺失,SVZ细胞数量显著减少。3)电镜示AQP4-/-小鼠室管膜细胞下层出现大量空泡样结构。4)野生型小鼠SVZ AQP4表达在出生后发育过程中逐渐升高。5)出生1天的AQP4+/+与AQP4-/-小鼠脑含水量无统计学差异,自出生后7天起至出生后56天,AQP4-/-小鼠脑含水量显著高于AQP4+/+小鼠。6)出生1天及7天的AQP4+/+与AQP4-/-小鼠LV容积、SVZ细胞密度无统计学差异;自出生后14天起至出生后56天,AQP4-/-小鼠LV容积、SVZ细胞密度则显著低于AQP4+/+小鼠。7)AQP4基因敲除显著减少成年小鼠脑脊液产量。
结论:AQP4基因敲除抑制成年小鼠SVZ神经干细胞增殖,破坏SVZ细胞排列结构,并减少脑脊液产量、增加脑含水量,表明AQP4参与成年小鼠SVZ神经干细胞增殖及SVZ结构形成的调控。
第二部分AQP4基因敲除对CD1小鼠SVZ成体神经干细胞自我更新、增殖、迁移、分化的影响
目的:研究、阐明AQP4对离体培养的小鼠SVZ成体神经干细胞自我更新、增殖、迁移、分化的影响及调控机制。
方法:分离培养2月龄AQP4+/+及AQP4-/-雄性小鼠SVZ ANSCs,应用神经球分析法(neurosphere assay)测定两种基因型ANSCs自我更新能力;采用BrdU掺入法测定ANSCs增殖能力;采用流式细胞仪法检测ANSCs细胞周期。将神经球贴壁生长48小时后测量ANSCs放射状迁移距离。用1% FCS诱导ANSCs分化7天后,采用Tuj-(1neuron-specific class IIIβ-tubulin)与GFAP(glial fibrillary acidic protein)免疫荧光双标法测定ANSCs向神经元及星形胶质细胞表型分化的比率。将ANSCs负载钙荧光探针Fluo 3-AM后采用激光共聚焦显微镜连续扫描,记录细胞内自发性钙振荡(spontaneous calcium oscillation)以及100 mM KCl所诱发的钙瞬变(calcium transient)。应用RT-PCR及Western blotting法检测神经干细胞L型、T型电压依赖性钙通道及缝隙连接蛋白Connexin43(Cx43)的表达。
结果:1)AQP4-/- ANSCs形成原代、第二代、第三代神经球的数量与大小以及BrdU标记阳性细胞比例均显著少于AQP4+/+ ANSCs。2)流式细胞仪检测结果显示AQP4基因敲除使凋亡期细胞比例增加,并出现G2/M细胞周期阻滞。3)AQP4-/- ANSCs放射状迁移距离显著短于AQP4+/+ ANSCs。4)AQP4基因敲除使ANSCs分化成Tuj-1阳性(神经元表型)细胞的比例显著低于AQP4+/+ ANSCs,两种基因型ANSCs分化成GFAP阳性(星形胶质细胞表型)细胞的比例无统计学差异。5)AQP4-/- ANSCs内自发性钙振荡的振幅显著低于AQP4+/+ ANSCs,频率显著快于AQP4+/+ ANSCs;AQP4-/- ANSCs经高钾诱导所产生钙瞬变峰值显著低于AQP4+/+ ANSCs。6)AQP4-/- ANSCs上L型电压依赖性钙通道Cav1.2及缝隙连接蛋白Cx43表达显著低于AQP4+/+ ANSCs。
结论:AQP4基因敲除抑制离体ANSCs自我更新、增殖、迁移及向神经元的分化,增强ANSCs自发性钙振荡的频率、减弱钙振荡振幅,抑制去极化所致胞内钙瞬变,表明AQP4通过调控细胞内钙动力学影响ANSCs生物学特性。
第三部分AQP4基因敲除对氟西汀促成年CD1小鼠SGZ神经再生作用的影响
目的:研究、阐明AQP4在氟西汀促SGZ神经再生及其抗抑郁效应中的作用与机制。
方法:1)经腹腔单次给予2-3月龄AQP4~+/+及AQP4~-/-雄性CD1小鼠氟西汀(10mg/kg),给药后0.25、5、12小时,分别取小鼠血浆及海马组织匀浆,用高效液相色谱法(high performance liquid chromatography,HPLC)测定氟西汀及其代谢产物去氧氟西汀的含量;2)经腹腔给予正常小鼠与慢性温和应激(chronic mild stress,CMS)致抑郁症模型小鼠氟西汀(10mg/kg),每日一次,持续四周。氟西汀给药结束前三天,采用新奇抑制摄食实验(novelty-suppressed feeding test,NSF)及悬尾实验(tail suspension test,TST)测定氟西汀对正常小鼠的抗焦虑效应;采用糖水偏爱(sucrose preference)实验及TST,评价氟西汀对抑郁症模型小鼠的抗抑郁效应。3)腹腔注射BrdU(50mg/kg,每两小时一次,共四次)24小时及28天后分批处死小鼠,灌注、取脑,行BrdU免疫组化/免疫荧光双重标记,通过计数SGZ BrdU阳性细胞数,NeuN/BrdU、GFAP/BrdU阳性细胞数测定海马神经干细胞增殖、存活及分化。4)取新鲜脑组织,匀浆后分别测定PKA、PKC活性,CREB、ERK1/2、CaMKⅣ磷酸化水平及AQP4表达水平。5)分离培养成年AQP4+/+及AQP4-/- CD1雄性小鼠海马ANSCs,采用[3H]thymidine掺入法测定0.1、1μM氟西汀对海马神经干细胞增殖的影响。
结果:1)单次氟西汀给药后0.25、5、12小时,两种基因型小鼠血浆及海马中氟西汀及去氧氟西汀的含量无统计学差异。2)AQP4基因敲除取消氟西汀的抗焦虑与抗抑郁作用。3)氟西汀能显著促进正常AQP4+/+小鼠SGZ细胞增殖,而对正常AQP4-/-小鼠SGZ细胞增殖无显著影响;氟西汀能逆转CMS造模对AQP4+/+小鼠SGZ细胞增殖的抑制作用,而对CMS造模所致AQP4-/-小鼠SGZ细胞增殖抑制无显著改善作用。4)AQP4基因敲除对BrdU标记阳性细胞存活的比例及其向神经元与星形胶质细胞分化的比例无显著影响。5)氟西汀能显著增强正常AQP4~+/+小鼠海马内CREB及CaMKⅣ磷酸化,而对正常AQP4-/-小鼠海马内CREB及CaMKⅣ磷酸化水平无显著影响;氟西汀对两种基因型正常小鼠海马ERK1/2磷酸化及PKA、PKC活性均无显著影响。6)CMS造模能抑制两种基因型小鼠海马中CREB、CaMKⅣ、ERK1/2磷酸化,抑制PKA活性,对PKC活性无显著影响;氟西汀能逆转CMS所致两种基因型小鼠海马内PKA活性及ERK1/2磷酸化水平的降低,对PKC活性无显著影响;氟西汀能逆转CMS造模所致AQP4+/+小鼠海马CREB、CaMKⅣ磷酸化水平的下降,而对AQP4-/-小鼠CREB、CaMKⅣ磷酸化水平的下降无显著改善作用。7)氟西汀能逆转CMS造模所致海马AQP4表达水平的升高。8)AQP4基因敲除显著抑制离体培养的成年小鼠SGZ海马神经干细胞增殖,并取消0.1μM、1μM氟西汀促ANSCs增殖效应。
结论:AQP4基因敲除抑制慢性氟西汀给药的促海马神经再生作用,进而取消氟西汀的抗抑郁效应,其机制可能与其抑制CaMKⅣ-CREB信号转导通路相关;氟西汀可能是脑内AQP4的调节剂。
综上所述,本文研究工作的主要创新之处在于:
1.发现AQP4参与成年小鼠SVZ神经干细胞增殖及SVZ结构形成的调控,为进一步研究脑内AQP4的病理生理作用积累了学术基础。
2.揭示AQP4是调节成年动物脑内神经再生的新靶点,为治疗神经再生障碍相关的神经精神疾病提供了新的思路。
3.阐明AQP4通过调节CaMKⅣ-CREB信号转导通路调制氟西汀促成年海马SGZ神经再生作用及抗抑郁效应。
4.发现氟西汀是脑内AQP4的调节剂,拓展了对脑内神经再生的分子调控及氟西汀药理作用机制的认识。
Aquaporins (AQPs) are integral membrane proteins that serve as channels in the transfer of water, and in some cases, small solutes across the membrane. So far, 13 aquaporin isoforms (AQP0-AQP12) have been identified in mammalian species. AQP4, the predominant isoform of AQPs in adult brain, is primarily expressed at the border between brain parenchyma and major fluid compartments, including astrocyte foot processes and glia limitans, as well as ependymal cells and subependymal astrocytes. The bidirectional water channel AQP4 has an important role in water homeostasis in the brain. It probably helps in the redistribution and absorption of edema fluid, because disruption of AQP4 is found to contribute to the pathophysiology of brain edema. AQP4 knockout markedly reduced brain swelling in mouse model of cytotoxic brain edema, whereas it significantly worsened outcome in mouse model of vasogenic brain edema. By using AQP4 knockout mice, increasing studies show that AQP4 is not only a specific water transporter, but also a mediator of astrocytic functions. Moreover, AQP4 is involved in regulating the homeostasis of microenvironment and neurotransmission in the brain.
The study of neurogenesis in the adult brain is the most exciting and fastest moving areas of neuroscience today. Adult neurogenesis mainly distributes in the subgranular zone (SGZ) of hippocampal dentate gyrus (DG) and the subventricular zone (SVZ) of the lateral ventricle. Neurogenesis is controlled by proliferation, differentiation, and migration of adult neural stem cells (ANSCs), which retain the potential to produce neurons, astrocytes, and oligodendrocytes. Under physiological condition, neurogenesis is thought to involve certain brain’s function, such as learning, memory, and mating behavior. Now, it has been demonstrated that neurogenesis is involved the pathogenesis of neuropsychiactric diseases and the fuction recovery after brain injury. For instance, promoting endogenous neurogenesis could improve neurological function in different stroke models. Chronic stress inhibits neurogenesis in SGZ, while antidepressants exert their therapeutic effects by increasing hippocampal neurogenesis. Therefore, promoting adult neurogenesis has been regarded as a prospective strategy for the treatment of neuropsychiatric diseases.
It is reported that AQP4 is extensively expressed in the brain regions such as SVZ and SGZ, where adult neurogenesis is found. Notably, AQP4 is the main subtype of AQPs in ANSCs. However, whether AQP4 participates the regulation of the biology of ANSCs and whether it is involved the adult neurogenesis under pathologic conditions remains unknown. In the present study, we first investigated the role of AQP4 in the cell proliferation and cyto-architecture of subventricular zone by using AQP4 knockout mice. Then, ANSCs from SVZ were cultured to study the role of AQP4 in cell self-renewal, proliferation, migration, and differentiation. Finally, AQP4 knockout mice were used to investigate whether AQP4 is involved in fluoxetine-induced enhancement of adult hippocampal neurogenesis under both basal and CMS-induced depressive conditions. The results revealed here will be beneficial to knowing the neurobiology of AQP4 in adult neurogenesis and provide a new target for developing therapeutic options for neuropsychiatric diseases.
Part I. Effects of AQP4 knockout on cell proliferation in SVZ/SGZ and cyto-architecture of SVZ
AIM: To investigate the role of AQP4 on cell proliferation in SVZ/SGZ and cyto-architecture of SVZ METHODS: Two-month-old wildtype (AQP4~+/+) and AQP4 knockout (AQP4~-/-) mice were injected intraperitoneally four times with BrdU (5-hydroxytryptamine, 50 mg/kg, i.p. q2h×4), and killed 24 hours after the last injection. The total number of BrdU-positive cells in the SVZ and SGZ were obtained stereologically by using the optical fractionator method. Dorsolateral parts (1.0×1.0mm) of the wall of lateral ventricles were post-fixed in 2% osmium and trimmed, and examined with electron microscope. AQP4+/+ and AQP4-/- mice at different age (postnatal 1 day, PN1, PN7, PN14, PN28, and PN56) were anesthetized and killed by cervical dislocation. Serial coronal sections through the rostro-caudal extent of the lateral ventricular (LV) were obtained by using a microtome. Sections were stained by hematoxylin-eosin (HE) or AQP4 immunohistochemistry. The cell density in SVZ and LV volume was determined by HE stained sections. The water content of forebrain was evaluated by wet-to-dry weight ratio with fresh forebrain tissues. Cerebrospinal fluid (CSF) production was evaluated by placing a piece of 1 mm×5 mm filter paper into cisterna magna and weighing.
RESULT: 1) AQP4 knockout significantly inhibited ANSCs proliferation in SVZ, but had no effect in SGZ. 2) In AQP4-/- mice, the volume of LV was significantly decreased, the ependymal layer was discontinuity, and cellular amount in subependymal layer was decreased. 3) Transmission electron micrograph showed many vacuolus in the SVZ of AQP4-/- mice. 4) The expression of AQP4 in SVZ increased during the postnatal development in AQP4+/+ mice. 5) The brain water content did not differ significantly between these two genotypic mice at PN1; since PN7 to PN56, the brain water content of AQP4-/- mice was significant higher than that of AQP4+/+ mice. 6) The cell density in SVZ did not differ significantly between these two genotypic mice at PN1 and PN7. Since PN14 to PN56, the brain water content of AQP4-/- mice was significant higher than that of AQP4+/+ mice. 6) The CSF production in adult AQP4-/- mice was significant lower than that of AQP4+/+ mice.
CONCLUSION: AQP4 knockout inhibites the proliferation of ANSCs in SVZ, disrupts the cyto-architecture of SVZ, decreases the CSF production, and increases the brain water conten. These results indicate that AQP4 is involved in the regulation of cell proliferation, structure formation of SVZ.
PartⅡ. Effects of AQP4 knockout on the self-renewal, proliferation, migration, and differentiation of adult neural stem cells in vitro
AIM: To investigate the effects and mechanisms of AQP4 on self-renewal, proliferation, migration, and differentiation of ANSCs in vitro. METHODS: ANSCs of 2-month-old AQP4+/+ and AQP4-/- mice were isolated and cultered from SVZ tissue. The self-renewal of ANSCs was measured by neurosphere assay. BrdU incorporation was used to investigate the proliferation of ANSCs, and cell cycle was determined by flow cytometry. Selected AQP4+/+ and AQP4-/- neurospheres with similar size were placed on coated 24-hole plate. The radial migration of ANSCs out of neurospheres was assayed 48 hours after plantation. Phenotypic Differentiation of ANSCs was determined by Tuj-1 (neuron-specific class IIIβ-tubulin) and GFAP (glial fibrillary acidic protein) double immunofluorescence after 7 days culture with 1% FCS. Intracellular spontaneous calcium oscillations and calcium transients induced by high concentration KCl were assayed by Fluo-3 calcium image. The expression of L-type and T-type votage-sensitive calcium channels and connexin 43 on ANSCs were determined by RT-PCR or western blot. RESULT: 1) The number and size of primary, secondary, and tertiary neurospheres generated from AQP4-/- ANSCs were significantly fewer and smaller than that of AQP4+/+ ANSCs. 2) The BrdU-positive cell in AQP4-/- ANSCs were significantly less than that of AQP4+/+ ANSCs. 3) AQP4 knockout increased basal apoptosis and induced G2/M arrest in ANSCs. 4) AQP4 knockout significantly attenuated radial migration of ANSCs out of neurospheres. 5) The proportion of Tuj-1-positive cells in AQP4-/- ANSCs culture was significantly lower than that of AQP4+/+ ANSCs culture after 7-day differentiation. The proportion of GFAP-positive cells did not differ significantly in both genotypic ANSCs cultures. 6) AQP4 knockout altered the spontaneous calcium oscillations by frequency enhancement and amplitude suppression, and suppressed KCl-induced calcium transient. 7) AQP4 knockout downregulated the expression of L-type voltage-gated calcium channel CaV1.2 subtype and the connexin43 in ANSCs.
CONCLUSION: AQP4 knockout inhibites ANSCs self-renewal, proliferation, migration and neuronal differentiation in vitro. Moreover, AQP4 knockout alters the spontaneous calcium oscillation in ANSCs by enhancement of frequency and decrement of amplitude, and inhibites depolarization-induced calcium transient. These findings show that AQP4 is involved in the regulation of the basic properties of ANSCs by modulating the intracellular calcium dynamics.
PartⅢ. Effects of AQP4 knockout on fluoxetine-induced enhancement of SGZ neurogenesis
AIM: To investigate the effects and mechanisms of AQP4 in fluoxetine-induced enhancement of SGZ neurogenesis and the antidepressive effects of fluoxetine METHODS: 1) Two to three-month-old AQP4+/+ and AQP4-/- mice were received a single i.p. injection of fluoxetine (10mg/kg). Concentrations of fluoxetine and its metabolite norfluoxetine in the plasma and hippocampus were measured at 0.25h, 5 h, and 12 h after fluoxetine injection by high performance liquid chromatography (HPLC). 2) AQP4+/+ and AQP4-/- CD1 male mice were subjected to daily i.p. injection of fluoxetine for 4 weeks under normal condition or followed by chronic mild stress (CMS). The anxiolytic effects of fluoxetine under normal condition were measured by novelty-suppressed feeding test (NSF) and tail suspension test (TST). The antidepressive effects of fluoxetine under stress were evaluated by sucrose preference test and TST. 3) BrdU was administrated to both genotypic mice followed 4-week fluoxetine treatment. Neurogenesis was evalutated by counting the BrdU-positive cells and NeuN/BrdU or GFAP/BrdU-positive cells in the SGZ. 4) Fresh hippocampal homogenates were used to determine the activities of PKA, PKC, the phosphoralations of CREB, ERK1/2, and CaMKⅣ, and the expression of AQP4. 5) The effects of fluoxetine (0.1, 1μM) on the proliferation of hippocampal ANSCs were assayed by [3H]thymidine incorporation.
RESULT: 1) The serum concentration or hippocampal content of fluoxetine and norfluoxetine did not differ significantly between AQP4+/+ and AQP4-/- mice at 0.25h, 5h, and 12h after single fluoxetine administration. 2) AQP4 knockout abolished anxiolytic and antidepressive effects of fluoxetine. 3) Under basal condition, 4-week treatment of fluoxetine increased the hippocampal neurogenesis in AQP4+/+ mice but failed in AQP4-/- mice. CMS procedure significantly inhibited hippocampal neurogenesis in both genotypic mice. Fluoxetine reversed CMS-induced hippocampal neurogenesis inhibition in AQP4+/+ mice, but the same treatment had no effect on AQP4-/- mice. 4) AQP4 knockout had no effect on the survival and differentiation of BrdU-positive cells in SGZ. 5) Under basal condition, fluoxetine treatment significantly enhanced phosphorylation of CREB and CaMKⅣin AQP4+/+ mice but not in AQP4-/- mice. The same treatment had no significant effect on the phosphorylation of ERK1/2 and the activities of PKA and PKC. 6) In both genotypic mice, CMS procedure significantly inhibited the phosphorylation of CREB, ERK1/2, CaMKⅣ, and the activity of PKA, but did not alter the activity of PKC. Four-week fluoxetine treatment reversed CMS-induced inhibition of ERK1/2 phosporylation and PKA activity, but did not alter the aictivity of PKC in both genotypic mice. Fluoxetine could restored CMS-induced decrement of CREB and CaMKⅣphosphorylation in AQP4+/+ mice, but failed in AQP4-/- mice. 7) Chronic fluoxetine treatment inhibited CMS-induced upregulation of hippocampal AQP4 expression in AQP4+/+ mice. 8) AQP4 knockout inhibited proliferation of ANSCs and abolished the pro-proliferative effects of fluoxetine in vitro.
CONCLUSION: AQP4 knockout cancels the antidepressive effects of fluoxetine by abolishing fluoxetine-induced enhancement of hippocampal SGZ neurogenesis. The underlying mechanism is attributed to that AQP4 knockout inhibites CaMKⅣ-CREB signal transduction. Moreover, fluoxetine may be a potential mediator for AQP4 expression.
In summary, the present work provides direct evidences for the first time that AQP4 plays an important role in adult neurogenesis.
1) AQP4 knockout inhibites the proliferation of ANSCs in SVZ, disrupts the cyto-architecture of SVZ, decreases the CSF production, and increases the brain water conten, which indicate that AQP4 is involved in the regulation of cell proliferation, structure formation of SVZ.
2) AQP4 knockout inhibites ANSCs self-renewal, proliferation, migration and neuronal differentiation in vitro. Moreover, AQP4 knockout alters the spontaneous calcium oscillation in ANSCs by enhancement of frequency and decrement of amplitude, and inhibites depolarization-induced calcium transient. These findings show that AQP4 is involved in the regulation of the basic properties of ANSCs by modulating the intracellular calcium dynamics.
3) AQP4 knockout cancels the antidepressive effects of fluoxetine by abolishing fluoxetine-induced enhancement of hippocampal SGZ neurogenesis. The underlying mechanism contributes to that AQP4 knockout inhibites CaMKⅣ-CREB signal transduction.
4) Fluoxetine may be a potential mediator for AQP4 expression.
成年神经再生(adult neurogenesis)是当今神经科学研究中最活跃、进展最快的领域之一。成年动物脑中侧脑室下区(subventricular zone,SVZ)与海马齿状回颗粒细胞下区(subgranular zone,SGZ)存在ANSCs,参与脑中持续的神经再生过程。ANSCs能自我更新、持续增殖并分化成神经元、星形胶质细胞和少突胶质细胞。生理状态下,神经再生参与学习记忆、择偶行为等多种脑高级功能的形成。在病理情况下,神经再生能力的改变参与多种神经精神疾病的发生及神经修复过程。例如,抑郁症患者SGZ神经再生减弱,抗抑郁药物可通过增强SGZ神经再生产生治疗学效应;增强脑卒中后神经再生能显著改善认知与运动功能缺损。但是,目前对于调节成年神经再生过程的分子机制认识非常有限。因此,探索成年神经再生的调节机制将为发展靶向于调制神经再生的药物提供新思路,为神经干细胞移植治疗积累学术基础。
近年来的研究发现,AQP4高度表达于SVZ、SGZ等神经再生显著的脑区,并且在鼠、猪及人类神经干细胞和神经祖细胞均有AQP4的表达。然而,AQP4是否参与调节成年神经再生?目前尚未见报道。因此,本文第一部分工作首先应用自行制备的AQP4基因敲除鼠在体研究AQP4基因敲除对SVZ/SGZ神经干细胞增殖及SVZ结构发育的影响;第二部分工作应用离体培养的小鼠SVZ ANSCs,研究AQP4基因敲除对ANSCs自我更新、增殖、迁移、分化等生物学特性的影响及其调节机制;第三部分工作在建立慢性温和应激(chronic mild stress,CMS)抑郁症模型小鼠的基础上,研究AQP4基因敲除对经典抗抑郁药物氟西汀(fluoxetine)促SGZ神经再生作用的影响及其相关的分子机制。研究结果开拓了AQP4神经生物学研究的新领域,深化对AQP4生理及病理功能的认识,揭示AQP4是调制成年神经再生的重要靶点,为研发针对神经修复的治疗药物提供新的靶标。
第一部分AQP4基因敲除对成年CD1小鼠SVZ/SGZ神经干细胞增殖及SVZ结构发育的影响
目的:研究、阐明AQP4在成年小鼠SVZ/SGZ神经干细胞增殖及SVZ结构发育中的作用。
方法:应用2月龄AQP4野生型(wildtype,AQP4~+/+)及AQP4基因敲除型(AQP4 knockout,AQP4-/-)雄性CD1小鼠,经腹腔给予5-溴-2-脱氧尿嘧啶核苷(5-bromo-2-deoxyuridine,BrdU,50mg/kg,每2小时一次,共4次)24小时后麻醉、灌注固定、取脑、冰冻切片,行BrdU免疫组化。取成年小鼠侧脑室(lateral ventricle,LV)背外侧区组织固定后行锇酸染色,电镜观察SVZ细胞结构。应用出生后1、7、14、28、56日龄AQP4+/+及AQP4-/- CD1小鼠,断头取脑,石蜡包埋后切取侧脑室前脚至中脑导水管出现部位冠状切片,行HE染色及AQP4免疫组化,测定LV容积、计数SVZ细胞密度,分析SVZ AQP4表达的灰度值。取新鲜全脑组织,用干/湿比重法测定脑含水量。取2月龄小鼠,打开小脑延髓池,用滤纸(1 mm×5 mm)称重法测定不同时间点脑脊液量。
结果:1)AQP4基因敲除显著抑制成年小鼠SVZ神经干细胞增殖,对SGZ神经干细胞增殖无显著影响。2)AQP4-/-小鼠侧脑室容积显著减小,室管膜层不连续,部分区域室管膜细胞缺失,SVZ细胞数量显著减少。3)电镜示AQP4-/-小鼠室管膜细胞下层出现大量空泡样结构。4)野生型小鼠SVZ AQP4表达在出生后发育过程中逐渐升高。5)出生1天的AQP4+/+与AQP4-/-小鼠脑含水量无统计学差异,自出生后7天起至出生后56天,AQP4-/-小鼠脑含水量显著高于AQP4+/+小鼠。6)出生1天及7天的AQP4+/+与AQP4-/-小鼠LV容积、SVZ细胞密度无统计学差异;自出生后14天起至出生后56天,AQP4-/-小鼠LV容积、SVZ细胞密度则显著低于AQP4+/+小鼠。7)AQP4基因敲除显著减少成年小鼠脑脊液产量。
结论:AQP4基因敲除抑制成年小鼠SVZ神经干细胞增殖,破坏SVZ细胞排列结构,并减少脑脊液产量、增加脑含水量,表明AQP4参与成年小鼠SVZ神经干细胞增殖及SVZ结构形成的调控。
第二部分AQP4基因敲除对CD1小鼠SVZ成体神经干细胞自我更新、增殖、迁移、分化的影响
目的:研究、阐明AQP4对离体培养的小鼠SVZ成体神经干细胞自我更新、增殖、迁移、分化的影响及调控机制。
方法:分离培养2月龄AQP4+/+及AQP4-/-雄性小鼠SVZ ANSCs,应用神经球分析法(neurosphere assay)测定两种基因型ANSCs自我更新能力;采用BrdU掺入法测定ANSCs增殖能力;采用流式细胞仪法检测ANSCs细胞周期。将神经球贴壁生长48小时后测量ANSCs放射状迁移距离。用1% FCS诱导ANSCs分化7天后,采用Tuj-(1neuron-specific class IIIβ-tubulin)与GFAP(glial fibrillary acidic protein)免疫荧光双标法测定ANSCs向神经元及星形胶质细胞表型分化的比率。将ANSCs负载钙荧光探针Fluo 3-AM后采用激光共聚焦显微镜连续扫描,记录细胞内自发性钙振荡(spontaneous calcium oscillation)以及100 mM KCl所诱发的钙瞬变(calcium transient)。应用RT-PCR及Western blotting法检测神经干细胞L型、T型电压依赖性钙通道及缝隙连接蛋白Connexin43(Cx43)的表达。
结果:1)AQP4-/- ANSCs形成原代、第二代、第三代神经球的数量与大小以及BrdU标记阳性细胞比例均显著少于AQP4+/+ ANSCs。2)流式细胞仪检测结果显示AQP4基因敲除使凋亡期细胞比例增加,并出现G2/M细胞周期阻滞。3)AQP4-/- ANSCs放射状迁移距离显著短于AQP4+/+ ANSCs。4)AQP4基因敲除使ANSCs分化成Tuj-1阳性(神经元表型)细胞的比例显著低于AQP4+/+ ANSCs,两种基因型ANSCs分化成GFAP阳性(星形胶质细胞表型)细胞的比例无统计学差异。5)AQP4-/- ANSCs内自发性钙振荡的振幅显著低于AQP4+/+ ANSCs,频率显著快于AQP4+/+ ANSCs;AQP4-/- ANSCs经高钾诱导所产生钙瞬变峰值显著低于AQP4+/+ ANSCs。6)AQP4-/- ANSCs上L型电压依赖性钙通道Cav1.2及缝隙连接蛋白Cx43表达显著低于AQP4+/+ ANSCs。
结论:AQP4基因敲除抑制离体ANSCs自我更新、增殖、迁移及向神经元的分化,增强ANSCs自发性钙振荡的频率、减弱钙振荡振幅,抑制去极化所致胞内钙瞬变,表明AQP4通过调控细胞内钙动力学影响ANSCs生物学特性。
第三部分AQP4基因敲除对氟西汀促成年CD1小鼠SGZ神经再生作用的影响
目的:研究、阐明AQP4在氟西汀促SGZ神经再生及其抗抑郁效应中的作用与机制。
方法:1)经腹腔单次给予2-3月龄AQP4~+/+及AQP4~-/-雄性CD1小鼠氟西汀(10mg/kg),给药后0.25、5、12小时,分别取小鼠血浆及海马组织匀浆,用高效液相色谱法(high performance liquid chromatography,HPLC)测定氟西汀及其代谢产物去氧氟西汀的含量;2)经腹腔给予正常小鼠与慢性温和应激(chronic mild stress,CMS)致抑郁症模型小鼠氟西汀(10mg/kg),每日一次,持续四周。氟西汀给药结束前三天,采用新奇抑制摄食实验(novelty-suppressed feeding test,NSF)及悬尾实验(tail suspension test,TST)测定氟西汀对正常小鼠的抗焦虑效应;采用糖水偏爱(sucrose preference)实验及TST,评价氟西汀对抑郁症模型小鼠的抗抑郁效应。3)腹腔注射BrdU(50mg/kg,每两小时一次,共四次)24小时及28天后分批处死小鼠,灌注、取脑,行BrdU免疫组化/免疫荧光双重标记,通过计数SGZ BrdU阳性细胞数,NeuN/BrdU、GFAP/BrdU阳性细胞数测定海马神经干细胞增殖、存活及分化。4)取新鲜脑组织,匀浆后分别测定PKA、PKC活性,CREB、ERK1/2、CaMKⅣ磷酸化水平及AQP4表达水平。5)分离培养成年AQP4+/+及AQP4-/- CD1雄性小鼠海马ANSCs,采用[3H]thymidine掺入法测定0.1、1μM氟西汀对海马神经干细胞增殖的影响。
结果:1)单次氟西汀给药后0.25、5、12小时,两种基因型小鼠血浆及海马中氟西汀及去氧氟西汀的含量无统计学差异。2)AQP4基因敲除取消氟西汀的抗焦虑与抗抑郁作用。3)氟西汀能显著促进正常AQP4+/+小鼠SGZ细胞增殖,而对正常AQP4-/-小鼠SGZ细胞增殖无显著影响;氟西汀能逆转CMS造模对AQP4+/+小鼠SGZ细胞增殖的抑制作用,而对CMS造模所致AQP4-/-小鼠SGZ细胞增殖抑制无显著改善作用。4)AQP4基因敲除对BrdU标记阳性细胞存活的比例及其向神经元与星形胶质细胞分化的比例无显著影响。5)氟西汀能显著增强正常AQP4~+/+小鼠海马内CREB及CaMKⅣ磷酸化,而对正常AQP4-/-小鼠海马内CREB及CaMKⅣ磷酸化水平无显著影响;氟西汀对两种基因型正常小鼠海马ERK1/2磷酸化及PKA、PKC活性均无显著影响。6)CMS造模能抑制两种基因型小鼠海马中CREB、CaMKⅣ、ERK1/2磷酸化,抑制PKA活性,对PKC活性无显著影响;氟西汀能逆转CMS所致两种基因型小鼠海马内PKA活性及ERK1/2磷酸化水平的降低,对PKC活性无显著影响;氟西汀能逆转CMS造模所致AQP4+/+小鼠海马CREB、CaMKⅣ磷酸化水平的下降,而对AQP4-/-小鼠CREB、CaMKⅣ磷酸化水平的下降无显著改善作用。7)氟西汀能逆转CMS造模所致海马AQP4表达水平的升高。8)AQP4基因敲除显著抑制离体培养的成年小鼠SGZ海马神经干细胞增殖,并取消0.1μM、1μM氟西汀促ANSCs增殖效应。
结论:AQP4基因敲除抑制慢性氟西汀给药的促海马神经再生作用,进而取消氟西汀的抗抑郁效应,其机制可能与其抑制CaMKⅣ-CREB信号转导通路相关;氟西汀可能是脑内AQP4的调节剂。
综上所述,本文研究工作的主要创新之处在于:
1.发现AQP4参与成年小鼠SVZ神经干细胞增殖及SVZ结构形成的调控,为进一步研究脑内AQP4的病理生理作用积累了学术基础。
2.揭示AQP4是调节成年动物脑内神经再生的新靶点,为治疗神经再生障碍相关的神经精神疾病提供了新的思路。
3.阐明AQP4通过调节CaMKⅣ-CREB信号转导通路调制氟西汀促成年海马SGZ神经再生作用及抗抑郁效应。
4.发现氟西汀是脑内AQP4的调节剂,拓展了对脑内神经再生的分子调控及氟西汀药理作用机制的认识。
Aquaporins (AQPs) are integral membrane proteins that serve as channels in the transfer of water, and in some cases, small solutes across the membrane. So far, 13 aquaporin isoforms (AQP0-AQP12) have been identified in mammalian species. AQP4, the predominant isoform of AQPs in adult brain, is primarily expressed at the border between brain parenchyma and major fluid compartments, including astrocyte foot processes and glia limitans, as well as ependymal cells and subependymal astrocytes. The bidirectional water channel AQP4 has an important role in water homeostasis in the brain. It probably helps in the redistribution and absorption of edema fluid, because disruption of AQP4 is found to contribute to the pathophysiology of brain edema. AQP4 knockout markedly reduced brain swelling in mouse model of cytotoxic brain edema, whereas it significantly worsened outcome in mouse model of vasogenic brain edema. By using AQP4 knockout mice, increasing studies show that AQP4 is not only a specific water transporter, but also a mediator of astrocytic functions. Moreover, AQP4 is involved in regulating the homeostasis of microenvironment and neurotransmission in the brain.
The study of neurogenesis in the adult brain is the most exciting and fastest moving areas of neuroscience today. Adult neurogenesis mainly distributes in the subgranular zone (SGZ) of hippocampal dentate gyrus (DG) and the subventricular zone (SVZ) of the lateral ventricle. Neurogenesis is controlled by proliferation, differentiation, and migration of adult neural stem cells (ANSCs), which retain the potential to produce neurons, astrocytes, and oligodendrocytes. Under physiological condition, neurogenesis is thought to involve certain brain’s function, such as learning, memory, and mating behavior. Now, it has been demonstrated that neurogenesis is involved the pathogenesis of neuropsychiactric diseases and the fuction recovery after brain injury. For instance, promoting endogenous neurogenesis could improve neurological function in different stroke models. Chronic stress inhibits neurogenesis in SGZ, while antidepressants exert their therapeutic effects by increasing hippocampal neurogenesis. Therefore, promoting adult neurogenesis has been regarded as a prospective strategy for the treatment of neuropsychiatric diseases.
It is reported that AQP4 is extensively expressed in the brain regions such as SVZ and SGZ, where adult neurogenesis is found. Notably, AQP4 is the main subtype of AQPs in ANSCs. However, whether AQP4 participates the regulation of the biology of ANSCs and whether it is involved the adult neurogenesis under pathologic conditions remains unknown. In the present study, we first investigated the role of AQP4 in the cell proliferation and cyto-architecture of subventricular zone by using AQP4 knockout mice. Then, ANSCs from SVZ were cultured to study the role of AQP4 in cell self-renewal, proliferation, migration, and differentiation. Finally, AQP4 knockout mice were used to investigate whether AQP4 is involved in fluoxetine-induced enhancement of adult hippocampal neurogenesis under both basal and CMS-induced depressive conditions. The results revealed here will be beneficial to knowing the neurobiology of AQP4 in adult neurogenesis and provide a new target for developing therapeutic options for neuropsychiatric diseases.
Part I. Effects of AQP4 knockout on cell proliferation in SVZ/SGZ and cyto-architecture of SVZ
AIM: To investigate the role of AQP4 on cell proliferation in SVZ/SGZ and cyto-architecture of SVZ METHODS: Two-month-old wildtype (AQP4~+/+) and AQP4 knockout (AQP4~-/-) mice were injected intraperitoneally four times with BrdU (5-hydroxytryptamine, 50 mg/kg, i.p. q2h×4), and killed 24 hours after the last injection. The total number of BrdU-positive cells in the SVZ and SGZ were obtained stereologically by using the optical fractionator method. Dorsolateral parts (1.0×1.0mm) of the wall of lateral ventricles were post-fixed in 2% osmium and trimmed, and examined with electron microscope. AQP4+/+ and AQP4-/- mice at different age (postnatal 1 day, PN1, PN7, PN14, PN28, and PN56) were anesthetized and killed by cervical dislocation. Serial coronal sections through the rostro-caudal extent of the lateral ventricular (LV) were obtained by using a microtome. Sections were stained by hematoxylin-eosin (HE) or AQP4 immunohistochemistry. The cell density in SVZ and LV volume was determined by HE stained sections. The water content of forebrain was evaluated by wet-to-dry weight ratio with fresh forebrain tissues. Cerebrospinal fluid (CSF) production was evaluated by placing a piece of 1 mm×5 mm filter paper into cisterna magna and weighing.
RESULT: 1) AQP4 knockout significantly inhibited ANSCs proliferation in SVZ, but had no effect in SGZ. 2) In AQP4-/- mice, the volume of LV was significantly decreased, the ependymal layer was discontinuity, and cellular amount in subependymal layer was decreased. 3) Transmission electron micrograph showed many vacuolus in the SVZ of AQP4-/- mice. 4) The expression of AQP4 in SVZ increased during the postnatal development in AQP4+/+ mice. 5) The brain water content did not differ significantly between these two genotypic mice at PN1; since PN7 to PN56, the brain water content of AQP4-/- mice was significant higher than that of AQP4+/+ mice. 6) The cell density in SVZ did not differ significantly between these two genotypic mice at PN1 and PN7. Since PN14 to PN56, the brain water content of AQP4-/- mice was significant higher than that of AQP4+/+ mice. 6) The CSF production in adult AQP4-/- mice was significant lower than that of AQP4+/+ mice.
CONCLUSION: AQP4 knockout inhibites the proliferation of ANSCs in SVZ, disrupts the cyto-architecture of SVZ, decreases the CSF production, and increases the brain water conten. These results indicate that AQP4 is involved in the regulation of cell proliferation, structure formation of SVZ.
PartⅡ. Effects of AQP4 knockout on the self-renewal, proliferation, migration, and differentiation of adult neural stem cells in vitro
AIM: To investigate the effects and mechanisms of AQP4 on self-renewal, proliferation, migration, and differentiation of ANSCs in vitro. METHODS: ANSCs of 2-month-old AQP4+/+ and AQP4-/- mice were isolated and cultered from SVZ tissue. The self-renewal of ANSCs was measured by neurosphere assay. BrdU incorporation was used to investigate the proliferation of ANSCs, and cell cycle was determined by flow cytometry. Selected AQP4+/+ and AQP4-/- neurospheres with similar size were placed on coated 24-hole plate. The radial migration of ANSCs out of neurospheres was assayed 48 hours after plantation. Phenotypic Differentiation of ANSCs was determined by Tuj-1 (neuron-specific class IIIβ-tubulin) and GFAP (glial fibrillary acidic protein) double immunofluorescence after 7 days culture with 1% FCS. Intracellular spontaneous calcium oscillations and calcium transients induced by high concentration KCl were assayed by Fluo-3 calcium image. The expression of L-type and T-type votage-sensitive calcium channels and connexin 43 on ANSCs were determined by RT-PCR or western blot. RESULT: 1) The number and size of primary, secondary, and tertiary neurospheres generated from AQP4-/- ANSCs were significantly fewer and smaller than that of AQP4+/+ ANSCs. 2) The BrdU-positive cell in AQP4-/- ANSCs were significantly less than that of AQP4+/+ ANSCs. 3) AQP4 knockout increased basal apoptosis and induced G2/M arrest in ANSCs. 4) AQP4 knockout significantly attenuated radial migration of ANSCs out of neurospheres. 5) The proportion of Tuj-1-positive cells in AQP4-/- ANSCs culture was significantly lower than that of AQP4+/+ ANSCs culture after 7-day differentiation. The proportion of GFAP-positive cells did not differ significantly in both genotypic ANSCs cultures. 6) AQP4 knockout altered the spontaneous calcium oscillations by frequency enhancement and amplitude suppression, and suppressed KCl-induced calcium transient. 7) AQP4 knockout downregulated the expression of L-type voltage-gated calcium channel CaV1.2 subtype and the connexin43 in ANSCs.
CONCLUSION: AQP4 knockout inhibites ANSCs self-renewal, proliferation, migration and neuronal differentiation in vitro. Moreover, AQP4 knockout alters the spontaneous calcium oscillation in ANSCs by enhancement of frequency and decrement of amplitude, and inhibites depolarization-induced calcium transient. These findings show that AQP4 is involved in the regulation of the basic properties of ANSCs by modulating the intracellular calcium dynamics.
PartⅢ. Effects of AQP4 knockout on fluoxetine-induced enhancement of SGZ neurogenesis
AIM: To investigate the effects and mechanisms of AQP4 in fluoxetine-induced enhancement of SGZ neurogenesis and the antidepressive effects of fluoxetine METHODS: 1) Two to three-month-old AQP4+/+ and AQP4-/- mice were received a single i.p. injection of fluoxetine (10mg/kg). Concentrations of fluoxetine and its metabolite norfluoxetine in the plasma and hippocampus were measured at 0.25h, 5 h, and 12 h after fluoxetine injection by high performance liquid chromatography (HPLC). 2) AQP4+/+ and AQP4-/- CD1 male mice were subjected to daily i.p. injection of fluoxetine for 4 weeks under normal condition or followed by chronic mild stress (CMS). The anxiolytic effects of fluoxetine under normal condition were measured by novelty-suppressed feeding test (NSF) and tail suspension test (TST). The antidepressive effects of fluoxetine under stress were evaluated by sucrose preference test and TST. 3) BrdU was administrated to both genotypic mice followed 4-week fluoxetine treatment. Neurogenesis was evalutated by counting the BrdU-positive cells and NeuN/BrdU or GFAP/BrdU-positive cells in the SGZ. 4) Fresh hippocampal homogenates were used to determine the activities of PKA, PKC, the phosphoralations of CREB, ERK1/2, and CaMKⅣ, and the expression of AQP4. 5) The effects of fluoxetine (0.1, 1μM) on the proliferation of hippocampal ANSCs were assayed by [3H]thymidine incorporation.
RESULT: 1) The serum concentration or hippocampal content of fluoxetine and norfluoxetine did not differ significantly between AQP4+/+ and AQP4-/- mice at 0.25h, 5h, and 12h after single fluoxetine administration. 2) AQP4 knockout abolished anxiolytic and antidepressive effects of fluoxetine. 3) Under basal condition, 4-week treatment of fluoxetine increased the hippocampal neurogenesis in AQP4+/+ mice but failed in AQP4-/- mice. CMS procedure significantly inhibited hippocampal neurogenesis in both genotypic mice. Fluoxetine reversed CMS-induced hippocampal neurogenesis inhibition in AQP4+/+ mice, but the same treatment had no effect on AQP4-/- mice. 4) AQP4 knockout had no effect on the survival and differentiation of BrdU-positive cells in SGZ. 5) Under basal condition, fluoxetine treatment significantly enhanced phosphorylation of CREB and CaMKⅣin AQP4+/+ mice but not in AQP4-/- mice. The same treatment had no significant effect on the phosphorylation of ERK1/2 and the activities of PKA and PKC. 6) In both genotypic mice, CMS procedure significantly inhibited the phosphorylation of CREB, ERK1/2, CaMKⅣ, and the activity of PKA, but did not alter the activity of PKC. Four-week fluoxetine treatment reversed CMS-induced inhibition of ERK1/2 phosporylation and PKA activity, but did not alter the aictivity of PKC in both genotypic mice. Fluoxetine could restored CMS-induced decrement of CREB and CaMKⅣphosphorylation in AQP4+/+ mice, but failed in AQP4-/- mice. 7) Chronic fluoxetine treatment inhibited CMS-induced upregulation of hippocampal AQP4 expression in AQP4+/+ mice. 8) AQP4 knockout inhibited proliferation of ANSCs and abolished the pro-proliferative effects of fluoxetine in vitro.
CONCLUSION: AQP4 knockout cancels the antidepressive effects of fluoxetine by abolishing fluoxetine-induced enhancement of hippocampal SGZ neurogenesis. The underlying mechanism is attributed to that AQP4 knockout inhibites CaMKⅣ-CREB signal transduction. Moreover, fluoxetine may be a potential mediator for AQP4 expression.
In summary, the present work provides direct evidences for the first time that AQP4 plays an important role in adult neurogenesis.
1) AQP4 knockout inhibites the proliferation of ANSCs in SVZ, disrupts the cyto-architecture of SVZ, decreases the CSF production, and increases the brain water conten, which indicate that AQP4 is involved in the regulation of cell proliferation, structure formation of SVZ.
2) AQP4 knockout inhibites ANSCs self-renewal, proliferation, migration and neuronal differentiation in vitro. Moreover, AQP4 knockout alters the spontaneous calcium oscillation in ANSCs by enhancement of frequency and decrement of amplitude, and inhibites depolarization-induced calcium transient. These findings show that AQP4 is involved in the regulation of the basic properties of ANSCs by modulating the intracellular calcium dynamics.
3) AQP4 knockout cancels the antidepressive effects of fluoxetine by abolishing fluoxetine-induced enhancement of hippocampal SGZ neurogenesis. The underlying mechanism contributes to that AQP4 knockout inhibites CaMKⅣ-CREB signal transduction.
4) Fluoxetine may be a potential mediator for AQP4 expression.
引文
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