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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

基本信息

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
项目类别：
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

项目摘要

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.