Late development of OCD-like phenotypes in Dlgap1 knockout mice.

IF 3.5 3区 医学 Q2 NEUROSCIENCES Psychopharmacology Pub Date : 2024-08-23 DOI:10.1007/s00213-024-06668-9
Kimino Minagawa, Takashi Hayakawa, Hayato Akimoto, Takuya Nagashima, Yasuo Takahashi, Satoshi Asai
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Abstract

Rationale: Despite variants in the Dlgap1 gene having the two lowest p-value in a genome-wide association study of obsessive compulsive disorder (OCD), previous studies reported the absence of OCD-like phenotypes in Dlgap1 knockout (KO) mice. Since these studies observed behavioral phenotypes only for a short period, development of OCD-like phenotypes in these mice at older ages was still plausible.

Objective: To examine the presence or absence of development of OCD-like phenotypes in Dlgap1 KO mice and their responsiveness to fluvoxamine.

Methods and results: Newly produced Dlgap1 KO mice were observed for a year. Modified SHIRPA primary screen in 2-month-old homozygous mutant mice showed only weak signs of anxiety, stress conditions and aggression. At older ages, however, these mutant mice exhibited excessive self-grooming characterized by increased scratching which led to skin lesions. A significant sex difference was observed in this scratching behavior. The penetrance of skin lesions reached 50% at 6-7 months of age and 90% at 12 months of age. In the open-field test performed just after the appearance of these lesions, homozygous mutant mice spent significantly less time in the center, an anxiety-like behavior, than did their wild-type and heterozygous littermates, none and less than 10% of which showed skin lesions at 1 year, respectively. The skin lesions and excessive self-grooming were significantly alleviated by two-week treatment with fluvoxamine.

Conclusion: Usefulness of Dlgap1 KO mice as a tool for investigating the pathogenesis of OCD-like phenotypes and its translational relevance was suggested.

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Dlgap1 基因敲除小鼠晚期出现强迫症样表型。
理由尽管在强迫症(OCD)的全基因组关联研究中,Dlgap1基因的变异具有两个最低的p值,但之前的研究报告称Dlgap1基因敲除(KO)小鼠没有OCD样表型。由于这些研究只观察到了小鼠短时间内的行为表型,因此这些小鼠在较大年龄时出现类似强迫症的表型仍然是有可能的:目的:研究 Dlgap1 KO 小鼠是否出现强迫症样表型及其对氟伏沙明的反应:对新生产的Dlgap1 KO小鼠进行为期一年的观察。对 2 个月大的同源突变小鼠进行修改后的 SHIRPA 初筛,结果显示它们只有微弱的焦虑、应激和攻击迹象。然而,在较大的年龄,这些突变小鼠表现出过度的自我梳理,其特点是抓挠增加,导致皮肤损伤。在这种抓挠行为中观察到了明显的性别差异。皮肤损伤的渗透率在 6-7 个月大时达到 50%,在 12 个月大时达到 90%。在皮损刚刚出现时进行的开阔地测试中,同卵突变体小鼠在中心花费的时间明显少于野生型和杂合子同窝小鼠,这是一种类似焦虑的行为,而野生型和杂合子同窝小鼠在1岁时分别没有皮损和只有不到10%的皮损。使用氟伏沙明治疗两周后,皮损和过度自我梳理的情况明显缓解:结论:Dlgap1 KO小鼠是研究强迫症样表型发病机制的有用工具,并具有转化意义。
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来源期刊
Psychopharmacology
Psychopharmacology 医学-精神病学
CiteScore
7.10
自引率
5.90%
发文量
257
审稿时长
2-4 weeks
期刊介绍: Official Journal of the European Behavioural Pharmacology Society (EBPS) Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields: Human Psychopharmacology: Experimental This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered. Human Psychopharmacology: Clinical and Translational This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects. Preclinical psychopharmacology: Behavioral and Neural This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels. Preclinical Psychopharmacology: Translational This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways. Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.
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