Role of subplate neurosecretion in early cortical circuit formation

板下神经分泌在早期皮质回路形成中的作用

• 批准号: MR/N026039/1
• 负责人: Zoltan Molnar
• 金额: $ 101.62万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN026039%2F1
• 关键词: Role; subplate; neurosecretion; early; cortical

The developing brain is not simply a smaller version of the adult's, but one that has a completely different composition, connectivity, and logic of processing information. The neuronal circuits in the neonate are set up to interpret neural signals while the construction of the brain is still ongoing, with certain cell populations present only during such formation stages. These early cells and their functions are key components for the eventual maturation of the brain similarly to the dynamic transient scaffolds used for the construction of complex buildings.We have a long-standing interest in studying these early-born cells and their involvement in both the normal and abnormal development of the brain. In particular, we focus on a transient compartment characterized by transient neuronal population and temporary synaptic connections called the subplate. Subplate cells are amongst the first born in the cerebral cortex, they initially represent a large cell group distributed in a zone between the site of neurogenesis and their final destination providing a platform for cortical development. However, these cells are only present during embryonic and early postnatal life and if the cortical development proceeds normally, they die at a particular stage. The transient nature of these cells highlights their importance in the assembly of a fully functional brain as well as their susceptibility to damage. We investigate the consequences of prematurity or perinatal brain damage on these cells, and the consequences of ablating them during the developmental time window for neurosecretion. With previous MRC grant funding during the past fourteen years, we characterised the early connections arriving to the cortex, gene expression patterns in subplate neurons at various developmental stages and also identified molecular markers for transient subplate neurons which now help us in the detailed study of these cells in animal models and in humans. This highlighted that many genes that are active in the subplate encode extracellular proteins. We recently described that subplate cells have the shape and intracellular machinery to secrete such proteins (Kondo et al., 2015). Protein secretation and vesicular release is downregulated following conditional knock-down of SNAP25 in subplate cells. Additionally, we demonstrated that one of these proteins - neuroserpin - is upregulated in a rat model of neonatal hypoxia-ischemia, as well as in normal brains at the peak of cell death. Combined with evidence from the adult stroke literature, this suggests that neuroserpin may play a neuroprotective role.We wish to capitalise on our previous achievements by identifying the role that secretion from subplate cells might play in normal brain development and in perinatal damage, particularly by testing whether neuroserpin can reduce the injury following hypoxia ischemia in mice.Our major objectives are:1. Characterise the timing and expression levels of neuroserpin and other secretory proteins in mice during development and after hypoxia. Study neuroserpin expression (mRNA and protein) in human.2. Prevent secretion from subplate cells by blocking regulated vesicle fusion or by removing subplate cells altogether from early postnatal stages and study the consequences this has on brain development.3. Study the effects of hypoxia in mice after viral delivery of neuroserpin into the brain or in neuroserpin knock-out mice.The outcome of this project will bring fundamental insights into the workings of brain development as well as its susceptibility and response to early brain injury. They will help to establish methods of ensuring healthy brain maturation by developing for the understanding necessary for effective treatments of brain damage after hypoxic ischemia and management of development in premature infants.

发育中的大脑不仅仅是成人大脑的缩小版，而是具有完全不同的组成、连接和处理信息的逻辑。新生儿的神经元回路是在大脑的构建仍在进行的同时建立起来的，以解释神经信号，某些细胞群只在这种形成阶段存在。这些早期细胞及其功能是大脑最终成熟的关键组成部分，类似于用于建造复杂建筑物的动态瞬态支架。我们长期以来一直对研究这些早期细胞及其在大脑正常和异常发育中的作用感兴趣。特别是，我们专注于一个短暂的车厢的特点是短暂的神经元群体和临时突触连接称为subplate。亚板细胞是最早在大脑皮层中诞生的细胞之一，它们最初代表分布在神经发生位点与其最终目的地之间的区域中的大细胞群，为皮层发育提供平台。然而，这些细胞只存在于胚胎和出生后早期，如果皮质发育正常，它们会在特定阶段死亡。这些细胞的瞬时性质突出了它们在组装功能齐全的大脑中的重要性以及它们对损伤的敏感性。我们研究了早产儿或围产期脑损伤对这些细胞的后果，以及在神经分泌发育时间窗内消融它们的后果。在过去的14年中，我们利用MRC的资助，描述了到达皮层的早期连接，不同发育阶段的亚板神经元中的基因表达模式，并确定了瞬时亚板神经元的分子标记物，这些标记物现在帮助我们在动物模型和人类中详细研究这些细胞。这突出表明，许多在亚板中活跃的基因编码细胞外蛋白。我们最近描述了亚板细胞具有分泌这类蛋白质的形状和细胞内机制（Kondo等人，2015年）的报告。在亚板细胞中，SNAP 25的条件性敲低后，蛋白质分泌和囊泡释放下调。此外，我们证明，这些蛋白质之一- neuroserpin -是上调的新生儿缺氧缺血大鼠模型，以及在正常的大脑细胞死亡的高峰。结合成人脑卒中文献的证据，这表明neuroserpin可能发挥神经保护作用。我们希望利用我们以前的成就，通过确定的作用，subplate细胞的分泌可能发挥在正常的脑发育和围产期损害，特别是通过测试neuroserpin是否可以减少小鼠缺氧缺血后的损伤。表征发育期间和缺氧后小鼠中神经丝氨酸蛋白酶抑制剂和其他分泌蛋白的时间和表达水平。研究神经丝氨酸蛋白酶抑制剂在人体中的表达（mRNA和蛋白质）.通过阻断受调节的囊泡融合或从出生后早期完全去除亚板细胞来防止亚板细胞的分泌，并研究这对大脑发育的影响。研究将神经丝氨酸蛋白酶抑制剂病毒导入小鼠大脑或神经丝氨酸蛋白酶抑制剂基因敲除小鼠后缺氧的影响。该项目的结果将为大脑发育的运作以及其对早期脑损伤的易感性和反应带来基本见解。他们将有助于建立确保健康的大脑成熟的方法，通过发展对缺氧缺血后脑损伤的有效治疗和早产儿发育管理所必需的理解。

项目成果

In search of common developmental and evolutionary origin of the claustrum and subplate

• DOI: 10.1002/cne.24922
• 发表时间: 2020-05-06
• 期刊: JOURNAL OF COMPARATIVE NEUROLOGY
• 影响因子: 2.5
• 作者: Bruguier, Hannah;Suarez, Rodrigo;Molnar, Zoltan
• 通讯作者: Molnar, Zoltan

Coupled Proliferation and Apoptosis Maintain the Rapid Turnover of Microglia in the Adult Brain.

耦合的增殖和凋亡维持成人大脑中小胶质细胞的快速离职。

• DOI: 10.1016/j.celrep.2016.12.041
• 发表时间: 2017-01-10
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Askew K;Li K;Olmos-Alonso A;Garcia-Moreno F;Liang Y;Richardson P;Tipton T;Chapman MA;Riecken K;Beccari S;Sierra A;Molnár Z;Cragg MS;Garaschuk O;Perry VH;Gomez-Nicola D
• 通讯作者: Gomez-Nicola D

The 100th Anniversary of the Russian Pavlov Physiological Society.

俄罗斯巴甫洛夫生理学会成立 100 周年。

• DOI: 10.1152/physiol.00023.2017
• 发表时间: 2017
• 期刊: Physiology (Bethesda, Md.)
• 作者: Brown RE

A comprehensive transcriptional map of primate brain development.

• DOI: 10.1038/nature18637
• 发表时间: 2016-07-21
• 期刊: Nature
• 影响因子: 64.8
• 作者: Bakken TE;Miller JA;Ding SL;Sunkin SM;Smith KA;Ng L;Szafer A;Dalley RA;Royall JJ;Lemon T;Shapouri S;Aiona K;Arnold J;Bennett JL;Bertagnolli D;Bickley K;Boe A;Brouner K;Butler S;Byrnes E;Caldejon S;Carey A;Cate S;Chapin M;Chen J;Dee N;Desta T;Dolbeare TA;Dotson N;Ebbert A;Fulfs E;Gee G;Gilbert TL;Goldy J;Gourley L;Gregor B;Gu G;Hall J;Haradon Z;Haynor DR;Hejazinia N;Hoerder-Suabedissen A;Howard R;Jochim J;Kinnunen M;Kriedberg A;Kuan CL;Lau C;Lee CK;Lee F;Luong L;Mastan N;May R;Melchor J;Mosqueda N;Mott E;Ngo K;Nyhus J;Oldre A;Olson E;Parente J;Parker PD;Parry S;Pendergraft J;Potekhina L;Reding M;Riley ZL;Roberts T;Rogers B;Roll K;Rosen D;Sandman D;Sarreal M;Shapovalova N;Shi S;Sjoquist N;Sodt AJ;Townsend R;Velasquez L;Wagley U;Wakeman WB;White C;Bennett C;Wu J;Young R;Youngstrom BL;Wohnoutka P;Gibbs RA;Rogers J;Hohmann JG;Hawrylycz MJ;Hevner RF;Molnár Z;Phillips JW;Dang C;Jones AR;Amaral DG;Bernard A;Lein ES
• 通讯作者: Lein ES

A missense mutation in Katnal1 underlies behavioural, neurological and ciliary anomalies.

• DOI: 10.1038/mp.2017.54
• 发表时间: 2018-03
• 期刊: Molecular psychiatry
• 影响因子: 11
• 作者: Banks G;Lassi G;Hoerder-Suabedissen A;Tinarelli F;Simon MM;Wilcox A;Lau P;Lawson TN;Johnson S;Rutman A;Sweeting M;Chesham JE;Barnard AR;Horner N;Westerberg H;Smith LB;Molnár Z;Hastings MH;Hirst RA;Tucci V;Nolan PM
• 通讯作者: Nolan PM