Upregulation of cholinergic modulators Lypd6 and Lypd6b associated with autism drives anxiety and cognitive decline.

IF 6.1 2区生物学 Q1 CELL BIOLOGY

Cell Death Discovery Pub Date : 2024-10-21 DOI:10.1038/s41420-024-02211-z

Aizek B Isaev, Maxim L Bychkov, Dmitrii S Kulbatskii, Alexander A Andreev-Andrievskiy, Mikhail A Mashkin, Mikhail A Shulepko, Olga V Shlepova, Eugene V Loktyushov, Alexander V Latanov, Mikhail P Kirpichnikov, Ekaterina N Lyukmanova

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Abstract

Intellectual disability and autistic features are associated with chromosome region 2q23.q23.2 duplication carrying LYPD6 and LYPD6B genes. Here, we analyzed LYPD6 and LYPD6B expression in patients with different neuropsychiatric disorders. Increased LYPD6 and LYPD6B expression was revealed in autism and other disorders. To study possible consequences of Lypd6 and Lypd6b overexpression in the brain, we used a mouse model with intracerebroventricular delivery of recombinant analogs of these proteins. A two-week infusion evoked significant memory impairment and acute stress. Both modulators downregulated hippocampal and amygdala dendritic spine density. No changes in synaptic plasticity were observed. Intracerebroventricular administration by both proteins downregulated hippocampal expression of Lypd6, Lypd6b, and α7 nicotinic acetylcholine receptor (nAChR). Similar to Lypd6, Lypd6b targeted different nAChR subtypes in the brain with preferential inhibition of α7- and α4β2-nAChRs. Thus, increased Lypd6 and Lypd6b level in the brain are linked to cholinergic system depression, neuronal atrophy, memory decline, and anxiety.

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与自闭症相关的胆碱能调节剂 Lypd6 和 Lypd6b 的上调会导致焦虑和认知能力下降。

智力障碍和自闭症特征与携带 LYPD6 和 LYPD6B 基因的染色体 2q23.q23.2 区域重复有关。在此，我们分析了 LYPD6 和 LYPD6B 在不同神经精神疾病患者中的表达情况。在自闭症和其他疾病中发现了 LYPD6 和 LYPD6B 表达的增加。为了研究 Lypd6 和 Lypd6b 在大脑中过度表达可能造成的后果，我们使用了一种小鼠模型，在小鼠脑室内注射这些蛋白的重组类似物。为期两周的输注诱发了明显的记忆损伤和急性应激。这两种调节剂都下调了海马和杏仁核树突棘密度。没有观察到突触可塑性的变化。这两种蛋白的脑室内给药会降低海马中Lypd6、Lypd6b和α7烟碱乙酰胆碱受体（nAChR）的表达。与Lypd6类似，Lypd6b也针对大脑中不同的nAChR亚型，优先抑制α7-和α4β2-nAChR。因此，大脑中 Lypd6 和 Lypd6b 水平的增加与胆碱能系统抑制、神经元萎缩、记忆力衰退和焦虑有关。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.