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(申请人提供)：在出生后的大脑发育过程中，抑制神经元回路的成熟和围绕GABA能中间神经元的周围神经网络(PNN)的形成导致了从幼年的、高度可塑性的可塑性形式向成年限制性形式的过渡。来自视觉皮质的新证据表明，正齿同源异型盒2(OTX2)蛋白在这种关键的发育转变中发挥了关键作用。在PNNS包裹的神经元中，OTX2的内化诱导其成熟，是开启和关闭可塑性关键期所必需的。PNNS，专门化细胞外基质结构 围绕不同的神经元群体，调节突触功能和可塑性，并维持成熟神经元细胞内的OTX2水平。越来越多的证据表明，OTX2/PNN的相互作用可能会影响到视觉皮质以外的大脑区域，包括杏仁核和前额叶皮质(PFC)。值得注意的是，OTX2不是在成人大脑中产生的。啮齿类动物的研究结果和人类的初步数据表明，脉络丛(CHP)是OTX2的全球来源，这意味着脑实质外OTX2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耐人寻味的可能性，即CHP衍生的OTX2可能调节抑制神经元电路和成人形式的可塑性，这一概念具有深远的生理、病理和治疗意义。值得注意的是，这一机制中的每一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，以及脑脊液(CSF)/血屏障，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已被报道在几个脑区，包括杏仁核和PFC，参与认知和情绪处理的脑区，以及SZ的病理生理学。3)初步证据显示SZ受试者脑脊液、杏仁核和前额叶中OTX2含量降低。我们推测，CHP来源的OTX2的缺陷与影响SZ的GABA能中间神经元和PNNS的异常可能是机械联系的。拟议的研究采用了一种互补的、真正的翻译方法，结合了对死后杏仁核、PFC、视觉皮质和脑脊液的人类研究和对人类CHP上皮细胞的体外研究，以及动物模型方法，包括小鼠的条件性基因靶向和全细胞电生理学。这些研究将检验这样一种假设，即源自CHP的OTX2对PFC和杏仁核的神经元成熟和电路可塑性至关重要。特别是，我们推测OTX2影响GABA能神经元周围PNN的成熟和维持，以及它们的功能和行为相关。在SZ，我们假设OTX2缺陷发生在CHP和CSF以及杏仁核和PFC中，与PNN丢失和GABA能神经元异常有关。这些研究中测试的通过CP对这些机制进行系统调节的可能性，可能会拓宽我们对大脑可塑性的理解，并开辟治疗SZ的新方法。