通过在关键期后增加皮质中间神经元的活动来改善脆性 X 小鼠的感觉缺陷。
Improvement of sensory deficits in fragile X mice by increasing cortical interneuron activity after the critical period.
机构信息
Department of Neurology, UCLA, Los Angeles, CA, USA.
Department of Pathology, UC Davis, Davis, CA, USA.
出版信息
Neuron. 2023 Sep 20;111(18):2863-2880.e6. doi: 10.1016/j.neuron.2023.06.009. Epub 2023 Jul 13.
Abstract
Changes in the function of inhibitory interneurons (INs) during cortical development could contribute to the pathophysiology of neurodevelopmental disorders. Using all-optical in vivo approaches, we find that parvalbumin (PV) INs and their immature precursors are hypoactive and transiently decoupled from excitatory neurons in postnatal mouse somatosensory cortex (S1) of Fmr1 KO mice, a model of fragile X syndrome (FXS). This leads to a loss of parvalbumin INs (PV-INs) in both mice and humans with FXS. Increasing the activity of future PV-INs in neonatal Fmr1 KO mice restores PV-IN density and ameliorates transcriptional dysregulation in S1, but not circuit dysfunction. Critically, administering an allosteric modulator of Kv3.1 channels after the S1 critical period does rescue circuit dynamics and tactile defensiveness. Symptoms in FXS and related disorders could be mitigated by targeting PV-INs.
摘要
在皮质发育过程中抑制性中间神经元 (INs) 的功能变化可能导致神经发育障碍的病理生理学改变。使用全光学体内方法，我们发现脆性 X 综合征 (FXS) 模型 Fmr1 KO 小鼠的出生后体感皮层 (S1) 中的 PV 中间神经元及其未成熟前体表现出低活性，并与兴奋性神经元短暂分离。这导致 FXS 小鼠和人类的 PV 中间神经元 (PV-INs) 丢失。在新生 Fmr1 KO 小鼠中增加未来 PV-IN 的活性可恢复 PV-IN 密度并改善 S1 中的转录失调，但不能改善电路功能障碍。至关重要的是，在 S1 关键期后施用 Kv3.1 通道的变构调节剂可挽救电路动力学和触觉防御。通过靶向 PV-INs 可以减轻 FXS 和相关疾病的症状。
相似文献
1
Improvement of sensory deficits in fragile X mice by increasing cortical interneuron activity after the critical period.通过在关键期后增加皮质中间神经元的活动来改善脆性 X 小鼠的感觉缺陷。
Neuron. 2023 Sep 20;111(18):2863-2880.e6. doi: 10.1016/j.neuron.2023.06.009. Epub 2023 Jul 13.
2
Tactile Defensiveness and Impaired Adaptation of Neuronal Activity in the Knock-Out Mouse Model of Autism.自闭症基因敲除小鼠模型中的触觉防御及神经元活动适应性受损
J Neurosci. 2017 Jul 5;37(27):6475-6487. doi: 10.1523/JNEUROSCI.0651-17.2017. Epub 2017 Jun 12.
3
Deletion of Fmr1 in parvalbumin-expressing neurons results in dysregulated translation and selective behavioral deficits associated with fragile X syndrome.在表达 Parvalbumin 的神经元中删除 Fmr1 会导致与脆性 X 综合征相关的翻译失调和选择性行为缺陷。
Mol Autism. 2022 Jun 29;13(1):29. doi: 10.1186/s13229-022-00509-2.
4
Functional consequences of postnatal interventions in a mouse model of Fragile X syndrome.脆性 X 综合征小鼠模型中产后干预的功能后果。
Neurobiol Dis. 2022 Jan;162:105577. doi: 10.1016/j.nbd.2021.105577. Epub 2021 Dec 4.
5
Delayed Maturation of Fast-Spiking Interneurons Is Rectified by Activation of the TrkB Receptor in the Mouse Model of Fragile X Syndrome.在脆性X综合征小鼠模型中，TrkB受体激活可纠正快速放电中间神经元的延迟成熟。
J Neurosci. 2017 Nov 22;37(47):11298-11310. doi: 10.1523/JNEUROSCI.2893-16.2017. Epub 2017 Oct 16.
6
Deletion of Fmr1 from Forebrain Excitatory Neurons Triggers Abnormal Cellular, EEG, and Behavioral Phenotypes in the Auditory Cortex of a Mouse Model of Fragile X Syndrome.从大脑兴奋性神经元中删除 Fmr1 会引发脆性 X 综合征小鼠模型听觉皮层中的异常细胞、EEG 和行为表型。
Cereb Cortex. 2020 Mar 14;30(3):969-988. doi: 10.1093/cercor/bhz141.
7
Genetic Reduction of Matrix Metalloproteinase-9 Promotes Formation of Perineuronal Nets Around Parvalbumin-Expressing Interneurons and Normalizes Auditory Cortex Responses in Developing Fmr1 Knock-Out Mice.基质金属蛋白酶-9 的遗传减少促进了表达 Parvalbumin 的中间神经元周围的神经周细胞网的形成，并使发育中的 Fmr1 敲除小鼠的听觉皮层反应正常化。
Cereb Cortex. 2018 Nov 1;28(11):3951-3964. doi: 10.1093/cercor/bhx258.
8
Reduced perineuronal net expression in Fmr1 KO mice auditory cortex and amygdala is linked to impaired fear-associated memory.Fmr1 KO 小鼠听觉皮层和杏仁核中少突胶质细胞相关蛋白聚糖表达减少与恐惧相关记忆受损有关。
Neurobiol Learn Mem. 2019 Oct;164:107042. doi: 10.1016/j.nlm.2019.107042. Epub 2019 Jul 18.
9
Fragile X cortex is characterized by decreased parvalbumin-expressing interneurons.脆性 X 皮层的特征是表达 parvalbumin 的中间神经元减少。
Cereb Cortex. 2024 Mar 1;34(3). doi: 10.1093/cercor/bhae103.
10
Impaired perceptual learning in a mouse model of Fragile X syndrome is mediated by parvalbumin neuron dysfunction and is reversible.脆性 X 综合征小鼠模型中感觉学习受损是由颗粒蛋白神经元功能障碍介导的，且是可逆转的。
Nat Neurosci. 2018 Oct;21(10):1404-1411. doi: 10.1038/s41593-018-0231-0. Epub 2018 Sep 24.
引用本文的文献
1
Syngap1 regulates the synaptic drive and membrane excitability of Parvalbumin-positive interneurons in mouse auditory cortex.Syngap1调节小鼠听觉皮层中小清蛋白阳性中间神经元的突触驱动和膜兴奋性。
Elife. 2025 Aug 14;13:RP97100. doi: 10.7554/eLife.97100.
2
Dentate gyrus network regulation by somatostatin- and parvalbumin-expressing interneurons differentially impacts hippocampal spatial memory processing.表达生长抑素和小白蛋白的中间神经元对齿状回网络的调节对海马体空间记忆处理有不同影响。
bioRxiv. 2025 Jul 24:2025.07.23.666335. doi: 10.1101/2025.07.23.666335.
3
Loss of FMRP in microglia promotes degeneration of parvalbumin neurons and audiogenic seizures via progranulin insufficiency.小胶质细胞中FMRP的缺失通过颗粒前体蛋白不足促进小白蛋白神经元变性和听源性癫痫发作。
bioRxiv. 2025 Jul 12:2025.07.09.663876. doi: 10.1101/2025.07.09.663876.
4
Dynamic recruitment of PV interneurons in the somatosensory cortex induced by experience dependent plasticity.由经验依赖性可塑性诱导的体感皮层中PV中间神经元的动态募集。
bioRxiv. 2025 Jun 28:2025.06.27.662081. doi: 10.1101/2025.06.27.662081.
5
Disruptions in primary visual cortex physiology and function in a mouse model of Timothy syndrome.蒂莫西综合征小鼠模型中初级视觉皮层生理和功能的破坏。
Cereb Cortex. 2025 Jun 4;35(6). doi: 10.1093/cercor/bhaf162.
6
Rethinking Sensory Information Processing: The Essential Role of Astrocytes.重新思考感觉信息处理：星形胶质细胞的重要作用。
J Neurochem. 2025 Jun;169(6):e70113. doi: 10.1111/jnc.70113.
7
Perinatal serotonin signalling dynamically influences the development of cortical GABAergic circuits with consequences for lifelong sensory encoding.围产期血清素信号动态影响皮质GABA能回路的发育，对终身感觉编码产生影响。
Nat Commun. 2025 Jun 4;16(1):5203. doi: 10.1038/s41467-025-59659-5.
8
A reduced ability to discriminate social from non-social touch at the circuit level may underlie social avoidance in autism.在神经回路层面上，区分社交性触摸与非社交性触摸的能力下降可能是自闭症患者社交回避行为的潜在原因。
Nat Commun. 2025 May 17;16(1):4600. doi: 10.1038/s41467-025-59852-6.
9
Targeting GABA Polarity During Cortical Development Improves Circuit and Sensory Deficits in Fragile X Mice.在皮层发育过程中靶向γ-氨基丁酸极性可改善脆性X小鼠的神经回路和感觉缺陷。
Biol Psychiatry. 2025 Mar 1;97(5):420-421. doi: 10.1016/j.biopsych.2024.12.006.
10
Iodine Deficiency Exacerbates Thyroidal and Neurological Effects of Developmental Perchlorate Exposure in the Neonatal and Adult Rat.碘缺乏会加剧新生和成年大鼠发育过程中高氯酸盐暴露对甲状腺和神经系统的影响。
Toxics. 2024 Nov 23;12(12):842. doi: 10.3390/toxics12120842.
本文引用的文献
1
Cortical interneurons in autism.自闭症中的皮质中间神经元。
Nat Neurosci. 2021 Dec;24(12):1648-1659. doi: 10.1038/s41593-021-00967-6. Epub 2021 Nov 29.
2
The organization and development of cortical interneuron presynaptic circuits are area specific.皮质中间神经元突触前回路的组织和发育具有区域特异性。
Cell Rep. 2021 Nov 9;37(6):109993. doi: 10.1016/j.celrep.2021.109993.
3
NMDARs Drive the Expression of Neuropsychiatric Disorder Risk Genes Within GABAergic Interneuron Subtypes in the Juvenile Brain.N-甲基-D-天冬氨酸受体驱动幼龄大脑中γ-氨基丁酸能中间神经元亚型内神经精神疾病风险基因的表达。
Front Mol Neurosci. 2021 Sep 14;14:712609. doi: 10.3389/fnmol.2021.712609. eCollection 2021.
4
clusterProfiler 4.0: A universal enrichment tool for interpreting omics data.clusterProfiler 4.0：用于解释组学数据的通用富集工具。
Innovation (Camb). 2021 Jul 1;2(3):100141. doi: 10.1016/j.xinn.2021.100141. eCollection 2021 Aug 28.
5
A human forebrain organoid model of fragile X syndrome exhibits altered neurogenesis and highlights new treatment strategies.脆性 X 综合征的人类大脑器官模型表现出神经发生改变，并突出了新的治疗策略。
Nat Neurosci. 2021 Oct;24(10):1377-1391. doi: 10.1038/s41593-021-00913-6. Epub 2021 Aug 19.
6
Somatostatin interneurons restrict cell recruitment to retinally driven spontaneous activity in the developing cortex.生长抑素中间神经元限制了细胞募集到视网膜驱动的发育皮层中的自发性活动。
Cell Rep. 2021 Jul 6;36(1):109316. doi: 10.1016/j.celrep.2021.109316.
7
Barrel cortex plasticity after photothrombotic stroke involves potentiating responses of pre-existing circuits but not functional remapping to new circuits.光血栓性中风后桶状皮层的可塑性涉及增强预先存在的回路的反应，但不是对新回路的功能重新映射。
Nat Commun. 2021 Jun 25;12(1):3972. doi: 10.1038/s41467-021-24211-8.
8
Cellpose: a generalist algorithm for cellular segmentation.Cellpose：一种通用的细胞分割算法。
Nat Methods. 2021 Jan;18(1):100-106. doi: 10.1038/s41592-020-01018-x. Epub 2020 Dec 14.
9
Postnatal connectomic development of inhibition in mouse barrel cortex.鼠桶状皮层抑制的产后连接组学发育。
Science. 2021 Jan 29;371(6528). doi: 10.1126/science.abb4534. Epub 2020 Dec 3.
10
Transient cortical circuits match spontaneous and sensory-driven activity during development.发育过程中，短暂的皮质电路与自发活动和感觉驱动活动相匹配。
Science. 2020 Oct 16;370(6514). doi: 10.1126/science.abb2153.
Zotero 插件