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（由适用提供）：在产后大脑发育期间，抑制性神经元回路的成熟以及围绕GABA能中间神经元周围的神经元网（PNN）形成，从而导致少年，高度可行的可变形式到成人受限模态。来自视觉皮层的新兴证据表明，在此类关键发育过渡中，orthodonicle同型2（OTX2）蛋白的关键作用。由PNN所示的神经元中的OTX2内在化诱导其成熟，并且有必要打开，近距离，关键时期的可塑性。 PNN，专门的细胞外基质结构 围绕不同的神经元种群，调节突触功能和可塑性，并在成熟的神经元中维持细胞内OTX2水平。融合的证据表明，OTX2/PNN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，OTX2不是在成年大脑内产生的。啮齿动物的结果和人类的初步数据指向脉络丛（CHP）是OTX2的全球源，这意味着在脑实质外改变OTX2合成可能会对关键的神经元功能产生深远的影响。总之，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元回路和成人形式的可塑性，这是具有深远的生理，病理和治疗意义的概念。值得注意的是，这种机制的每个元素都对精神分裂症（SZ）的病理生理学特别感兴趣：i）CHP的参与，脑脊液（CSF）/血液屏障一直怀疑，尽管近年来有些被忽略了。 ii）在包括杏仁核和PFC在内的几个大脑区域中，GABA能神经元和PNN异常已报道，涉及认知和情感处理的大脑区域以及SZ的病理生理学。 iii）初步证据表明，患有SZ受试者的CSF，杏仁核和PFC的OTX2降低。我们假设可以机械连接CHP来源的OTX2和影响SZ中GABA能中间神经元和PNN的异常。拟议的调查员工是一种完整的，真正翻译的方法，将人类有关人类杏仁核，PFC，Visual Cortex和CSF的研究结合在一起，以及对人类CHP上皮细胞的体外研究，以及包括小鼠中有条件基因靶向的动物模型方法，以及全细胞电学物理学。这些研究将检验以下假设：源自CHP的OTX2对PFC和Amygdala中神经元成熟和电路可塑性至关重要。特别是，我们假设OTX2会影响GABA能神经元及其功能和行为相关的PNN的成熟和维持。在SZ中，我们假设OTX2缺陷出现在CHP和CSF中，以及与PNN丧失和GABAergic神经元异常有关的杏仁核和PFC中。在这些研究中测试的CP进行全身调节这些机制的潜力可能会扩大我们对大脑可塑性和开放式SZ的新型治疗方法的理解。