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）：在出生后的大脑发育过程中，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网（PNN）的形成导致可塑性从幼年的高度可塑性形式转变为成年的受限形式。来自视觉皮层的新证据指出了正齿体同源框2（OTX 2）蛋白在这种关键的发育过渡中的关键作用。在由PNN包裹的神经元中的OTX 2内化诱导它们的成熟，并且是打开然后关闭可塑性的关键时期所必需的。PNN，特化细胞外基质结构 在不同的神经元群体周围，调节突触功能和可塑性，并维持成熟神经元中的细胞内OTX 2水平。越来越多的证据表明，OTX 2/PNN的相互作用可能会影响视觉皮层以外的大脑区域，包括杏仁核和前额叶皮层（PFC）。值得注意的是，OTX 2不在成人大脑中产生。来自啮齿动物的结果和人类的初步数据表明，脉络丛（ChP）是OTX 2的全球来源，这意味着脑实质外OTX 2合成的改变可能对关键神经元功能产生深远影响。总之，这些发现表明了一种有趣的可能性，即ChP衍生的OTX 2的可用性可能调节抑制性神经元回路和成人形式的可塑性，这是一个具有深远生理学，病理学和治疗意义的概念。值得注意的是，这种机制的每个元素都是精神分裂症（SZ）的病理生理学特别感兴趣：I）ChP和脑脊液（CSF）/血液屏障的参与，长期以来一直被怀疑，尽管近年来有些被忽视。II）GABA能神经元和PNN异常已经在几个脑区域中报道，包括杏仁核和PFC，涉及认知和情感处理以及SZ的病理生理学的脑区域。III）初步证据显示SZ受试者的CSF、杏仁核和PFC中的OTX 2减少。我们推测，ChP衍生的OTX 2和影响SZ中GABA能中间神经元和PNNs的异常的缺陷可能是机械相关的。拟议的调查采用了一种互补的，真正的翻译方法，结合人体研究死后杏仁核，PFC，视觉皮层和CSF和体外研究人类ChP上皮细胞，动物模型的方法，包括条件基因靶向小鼠，和全细胞电生理学。这些研究将检验以下假设：源自ChP的OTX 2对PFC和杏仁核中的神经元成熟和回路可塑性至关重要。特别地，我们假设OTX 2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，我们假设与PNN损失和GABA能神经元异常相关的ChP和CSF以及杏仁核和PFC中发生OTX 2缺陷。在这些研究中，通过CP对这些机制进行系统调节的潜力可能会拓宽我们对脑可塑性的理解，并为SZ开辟新的治疗方法。