Structural and Functional Alterations of Interneurons in Models of Schizophrenia

精神分裂症模型中中间神经元的结构和功能改变

基本信息

批准号：
8113673
负责人：
ISTVAN MODY
金额：
$ 23.1万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-10 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8113673
关键词：
Address Adult Affect American Antipsychotic Agents Axon Brain Brain region C-terminal Calcium-Binding Proteins Cells Characteristics Chondroitin ABC Lyase Cognitive Delusions Development Devices Diffusion Disinhibition Dominant-Negative Mutation Environmental Risk Factor Extracellular Matrix Failure Fluorescence Microscopy Functional disorder Genetic Glutamates Hallucinations Heterogeneity Hyperactive behavior Impaired cognition Impairment In Vitro Interneuron function Interneurons Knock-out Knockout Mice Lateral Lead Link Mediating Membrane Mental disorders Microscopy Modeling Morphology Mus N-Methyl-D-Aspartate Receptors Neurons Neurotransmitters Occupational Output Parvalbumins Patients Pattern Peptide Hydrolases Physiologic pulse Plastics Population Process Property Prosencephalon Pyramidal Cells Resolution Role Schizophrenia Secondary to Signal Pathway Signal Transduction Structure Symptoms Synapses Syndrome System Tamoxifen Therapeutic Time Transgenic Mice calmodulin-dependent protein kinase II cell type cholinergic cognitive function design excitatory neuron experience extracellular gamma-Aminobutyric Acid hippocampal pyramidal neuron insight light microscopy malformation mouse model neuronal cell body patch clamp postsynaptic presynaptic receptor receptor-mediated signaling social tissue fixing transmission process treatment strategy voltage clamp

项目摘要

DESCRIPTION (provided by applicant): Schizophrenia is associated with a reduction in GABA synthesis in a subpopulation of cortical interneurons that express the calcium-binding protein, parvalbumin (PV). These inhibitory interneurons display fast-spiking properties and target the perisomatic domain and axon initial segment of excitatory pyramidal neurons, thus enabling exquisite control over their spike timing. A deficit in such perisomatic inhibition in schizophrenia is likely to contribute to the impairments of fast cortical network synchronization and higher cognitive processing, which are key features of this disabling mental disorder. Another distinguishing characteristic of cortical PV interneurons are the dense aggregates of extracellular matrix molecules that ensheath their somata and primary processes, appearing as perineuronal nets (PNNs). The formation and degradation of these PNNs are activity-dependent, but their function and modulation in schizophrenia remain unknown. Our hypotheses are that 1) PV interneuron plasticity in schizophrenia is related to structural remodeling of PNNs, and 2) dysfunction of reciprocal inhibition between PV interneurons, possibly secondary to the altered structure of PNNs, is a key component of GABAergic deficits in schizophrenia. We will use two recently characterized transgenic mouse models of schizophrenia: the tamoxifen-inducible expression of the dominant-negative DISC1 C-terminal fragment (DISC1-cc) in 1-CaMKII expressing neurons and the selective knockout of NMDA receptors in forebrain GABAergic interneurons (Ppp1r2-Cre x NR1loxP/loxP mice). The ultrastructure of PNNs surrounding afferent terminals on PV interneurons will be determined using stimulated emission depletion (STED) super-resolution microscopy (nanoscopy) in fixed tissue. A deficiency in the inhibitory output of cortical PV interneurons in schizophrenia is thought to lead to hyperactivity and hyposynchrony of excitatory pyramidal neurons, and contribute to deficits in cognitive function. PV interneurons also show dense reciprocal connectivity, but the possible pathophysiology of such mutual inhibition remains unexplored. Patch-clamp recordings from PV interneurons in vitro will elucidate how these multiple modes of reciprocal GABAergic signaling and intrinsic membrane properties are modified in mouse models of schizophrenia. We propose that remodeling of the PNNs surrounding PV interneurons, and the erosion of compartmentalized synaptic and extrasynaptic GABAergic signaling pathways are critical components of the cortical network disinhibition in schizophrenia. Understanding how the multiple facets of GABAergic inhibition are disturbed in schizophrenia is essential for the rational design of GABAergic therapeutics. Moreover, elucidating the particular role of PNNs in both the function and dysfunction of PV interneurons should inspire new treatment strategies targeting the proteases responsible for PNN degradation. PUBLIC HEALTH RELEVANCE: Schizophrenia is a debilitating mental disorder that affects ~2.4 million Americans, and ~1% of the world's adult population. This syndrome is thought to arise through an interaction of multiple genetic and environmental factors during brain development, leading to a persistent dysfunction of dopaminergic, glutamatergic, GABAergic and cholinergic neurotransmitter systems into adulthood. Current monoaminergic treatments for schizophrenia are most effective in treating positive symptoms, comprising hallucinations and/or delusions. However, such antipsychotics yield little amelioration of the burden of negative symptoms and cognitive impairments, which may have the greatest impact on patients' long-term social and occupational abilities. It has been suggested that cognitive dysfunction in schizophrenia might be more intimately linked with deficits in cortical GABAergic transmission. There is great potential for addressing such dysfunction, as GABAA receptors display a high degree of heterogeneity in subunit composition, which is reflected in distinct patterns of expression across cell types and brain regions, and confers the opportunity for selective pharmacological modulation. The rational design of GABAergic therapeutics, though, will require a more detailed understanding of how functional imbalances in the multiple facets of GABAA receptor-mediated signaling contribute to schizophrenic symptoms.

描述（由申请人提供）：精神分裂症与表达钙结合蛋白小清蛋白（PV）的皮质中间神经元亚群中 GABA 合成的减少有关。这些抑制性中间神经元表现出快速尖峰特性，并针对兴奋性锥体神经元的体周围域和轴突初始段，从而能够精确控制其尖峰时间。精神分裂症中这种躯体周围抑制的缺陷可能会导致快速皮质网络同步和高级认知处理的损害，这是这种致残性精神障碍的关键特征。皮质 PV 中间神经元的另一个显着特征是细胞外基质分子的致密聚集体，包裹着其体细胞和初级突起，表现为神经周围网 (PNN)。这些 PNN 的形成和降解是活动依赖性的，但它们在精神分裂症中的功能和调节仍然未知。我们的假设是：1）精神分裂症中的 PV 中间神经元可塑性与 PNN 的结构重塑有关，2）PV 中间神经元之间的相互抑制功能障碍（可能继发于 PNN 结构的改变）是精神分裂症中 GABA 能缺陷的关键组成部分。我们将使用两种最近表征的精神分裂症转基因小鼠模型：在表达 1-CaMKII 的神经元中他莫昔芬诱导表达显性失活 DISC1 C 末端片段 (DISC1-cc)，以及在前脑 GABA 能中间神经元中选择性敲除 NMDA 受体。 Ppp1r2-Cre x NR1loxP/loxP 小鼠）。 PV 中间神经元传入末梢周围 PNN 的超微结构将使用固定组织中的受激发射损耗 (STED) 超分辨率显微镜（纳米镜）来确定。精神分裂症患者皮质 PV 中间神经元抑制输出的缺陷被认为会导致兴奋性锥体神经元的过度活跃和不同步，并导致认知功能缺陷。 PV 中间神经元也表现出密集的相互连接，但这种相互抑制的可能病理生理学仍未被探索。体外 PV 中间神经元的膜片钳记录将阐明这些相互 GABA 信号传导和内在膜特性的多种模式如何在精神分裂症小鼠模型中发生改变。我们认为，PV 中间神经元周围 PNN 的重塑以及突触和突触外 GABA 信号通路的侵蚀是精神分裂症皮质网络去抑制的关键组成部分。了解精神分裂症中 GABA 能抑制的多个方面如何受到干扰对于合理设计 GABA 能疗法至关重要。此外，阐明 PNN 在 PV 中间神经元的功能和功能障碍中的特殊作用应该会激发针对负责 PNN 降解的蛋白酶的新治疗策略。公共卫生相关性：精神分裂症是一种使人衰弱的精神疾病，影响约 240 万美国人，约占世界成年人口的 1%。这种综合征被认为是大脑发育过程中多种遗传和环境因素相互作用而产生的，导致成年后多巴胺能、谷氨酸能、GABA能和胆碱能神经递质系统持续功能障碍。目前精神分裂症的单胺能治疗对于治疗阳性症状（包括幻觉和/或妄想）最有效。然而，此类抗精神病药物对阴性症状和认知障碍的负担几乎没有改善，而这可能对患者的长期社交和职业能力产生最大的影响。有人提出，精神分裂症的认知功能障碍可能与皮质 GABA 传递缺陷有更密切的关系。解决这种功能障碍具有巨大的潜力，因为 GABAA 受体在亚基组成上表现出高度的异质性，这反映在不同细胞类型和大脑区域的不同表达模式上，并为选择性药理调节提供了机会。然而，GABA 能疗法的合理设计需要更详细地了解 GABAA 受体介导的信号传导多个方面的功能失衡如何导致精神分裂症症状。