Choroid plexus and mis_regulation of brain OTX2 in schizophrenia

精神分裂症中脉络丛与脑OTX2的失调

• 批准号: 9230867
• 负责人: Sabina Berretta
• 金额: $ 47.13万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9230867
• 关键词: Acoustics; Adolescent; Adult; Affect; Amygdaloid structure; Animal Model; Autopsy; Behavioral; Blood; Brain; Brain Diseases; Brain region; Cell Culture Techniques; Cells; Cerebrospinal Fluid; Cognitive; Data; Development; Disease; Electrophysiology (science); Elements; Emotions; Ensure; Epithelial Cells; Extinction (Psychology); Extracellular Matrix; Feedback; Fright; Functional disorder; Gene Expression; Gene Targeting; Goals; Growth Factor; Homeobox; Homeodomain Proteins; Human; In Vitro; Interneurons; Investigation; Life; Link; Maintenance; Measures; Mediating; Messenger RNA; Modality; Mus; Mutant Strains Mice; Nervous system structure; Neurobiology; Neurons; Output; Pathologic; Physiological; Plasticizers; Population; Prefrontal Cortex; Process; Proteins; Regulation; Reporting; Research; Rodent; Role; Schizophrenia; Source; Stream; Structure; Structure of choroid plexus; Study models; Synaptic plasticity; Testing; Therapeutic; Time; Ursidae Family; Vascular blood supply; Visual Cortex; base; blood cerebrospinal fluid barrier; brain parenchyma; brain tissue; critical period; design; extracellular vesicles; immunoreactivity; interest; mouse model; neglect; neural circuit; neuronal circuitry; neurotrophic factor; novel; novel therapeutic intervention; peripheral blood; postnatal; preference; protein expression; public health relevance; relating to nervous system; synaptic function; transcription factor; translational approach; translational study; uptake

 DESCRIPTION (provided by applicant): During postnatal brain development, the maturation of inhibitory neuronal circuits and formation of perineuronal nets (PNNs) around GABAergic interneurons result in a transition from juvenile, highly malleable, forms of plasticity to adult restricted modalities. Emerging evidence from the visual cortex points to a key role for the orthodenticle homeobox 2 (OTX2) protein in such critical developmental transitions. OTX2 internalization in neurons ensheated by PNNs induces their maturation and is necessary to open, then close, critical periods of plasticity. PNNs, specialized extracellular matrix structures surrounding distinct neuronal populations, regulate synaptic functions and plasticity, and sustain intracellular OTX2 levels in mature neurons. Converging evidence suggests that OTX2/PNN interactions may affect brain regions beyond the visual cortex, including the amygdala and prefrontal cortex (PFC). Of note, OTX2 is not produced within the adult brain. Results from rodents, and preliminary data in human, point to the choroid plexus (ChP) as a global source of OTX2, implying that altered OTX2 synthesis outside the brain parenchyma may have a profound impact on key neuronal functions. Together, these findings suggest the intriguing possibility that availability of ChP-derived OTX2 may modulate inhibitory neuronal circuits and adult forms of plasticity, a concept with far-reaching physiological, pathological and therapeutic implications. Notably, each element of this mechanism is of particular interest to the pathophysiology of schizophrenia (SZ): I) Involvement of the ChP, and the cerebrospinal fluid (CSF)/blood barrier, have been long suspected, although somewhat neglected in recent years. II) GABAergic neuron and PNN abnormalities have been reported in several brain regions, including the amygdala and PFC, brain regions involved in cognitive and emotion processing and in the pathophysiology of SZ. III) Preliminary evidence shows OTX2 decreases in the CSF, amygdala and PFC of subjects with SZ. We postulate that deficits of ChP-derived OTX2 and abnormalities affecting GABAergic interneurons and PNNs in SZ may be mechanistically linked. The proposed investigations employ a complementary, truly translational approach, combining human studies on postmortem amygdala, PFC, visual cortex, and CSF and in vitro studies on human ChP epithelial cells, with animal model approaches including conditional gene-targeting in mice, and whole-cell electrophysiology. These investigations will test the hypothesis that OTX2 originating from the ChP is pivotal to neuronal maturation and circuit plasticity in the PFC and amygdala. In particular, we postulate that OTX2 affects maturation and maintenance of PNNs surrounding GABAergic neurons and their functional and behavioral correlates. In SZ, we hypothesize that OTX2 deficits occur in the ChP and CSF as well as in the amygdala and PFC in association with PNN loss and GABAergic neuron abnormalities. The potential for systemic modulation of these mechanisms through the CP, tested in these studies, may broaden our understanding of brain plasticity and open novel therapeutic approaches to SZ.

 描述（由申请人提供）：在出生后大脑发育过程中，抑制性神经元回路的成熟和 GABA 能中间神经元周围神经元周围网络 (PNN) 的形成导致从幼年、高度可塑性的可塑性形式向成人受限形式的转变。视觉皮层指出正牙齿同源盒 2 (OTX2) 蛋白在神经元 OTX2 内化的关键发育过程中发挥着关键作用。被 PNN 包裹会诱导其成熟，并且对于打开和关闭 PNN（特殊的细胞外基质结构）的可塑性关键时期是必要的。 围绕不同的神经群体，调节突触功能和可塑性，并维持成熟神经元的细胞内 OTX2 水平。 OTX2 不在成人大脑内产生。啮齿动物的结果和人类的初步数据表明脉络丛 (ChP) 是 OTX2 的整体来源，这意味着脉络丛发生了改变。脑实质外的 OTX2 合成可能对关键神经元功能产生深远的影响，这些发现表明 ChP 衍生的 OTX2 的可用性可能会调节抑制性神经回路和成人形式的可塑性，这是一个具有深远生理学意义的概念。值得注意的是，该机制的每个要素对于精神分裂症 (SZ) 的病理生理学特别重要：I) ChP 的参与，以及脑脊液（CSF）/血液屏障长期以来一直被怀疑，尽管近年来有些被忽视。 III) 初步证据显示 SZ 受试者的 CSF、杏仁核和 PFC 中 OTX2 减少。 ChP 衍生的 OTX2 和影响 SZ 中 GABA 能中间神经元和 PNN 的异常可能在机制上相关。拟议的研究采用了一种互补的、真正的转化方法，结合了对死后杏仁核、PFC、视觉皮层和 CSF 的人类研究以及对人类 ChP 的体外研究。上皮细胞，动物模型方法，包括小鼠条件基因靶向和全细胞电生理学，这些研究将检验 OTX2 起源于上皮细胞的假设。 ChP 对于 PFC 和杏仁核的神经元成熟和回路可塑性至关重要，特别是，我们假设 OTX2 影响 GABA 能神经元周围的 PNN 的成熟和维持及其功能和行为相关性。在 SZ 中，我们努力发现 OTX2 缺陷发生在 ChP 中。脑脊液以及杏仁核和 PFC 中与 PNN 丢失和 GABA 神经元异常相关的这些机制的系统调节潜力。这些研究中测试的 CP 可能会拓宽我们对大脑可塑性的理解，并为 SZ 开辟新的治疗方法。