Premorbid Characteristics of the SAPAP3 Mouse Model of Obsessive-Compulsive Disorder: Behavior, Neuroplasticity, and Psilocybin Treatment.

IF 4.5 2区 医学 Q1 CLINICAL NEUROLOGY
Michal Lazar, Michal Brownstien, Alexander Botvinnik, Chloe Shevakh, Orr Shahar, Tzuri Lifschytz, Bernard Lerer
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引用次数: 0

Abstract

Background: SAPAP3-knockout (SAPAP3-KO) mice develop excessive self-grooming behavior at 4-6 months of age, serving as a model for obsessive-compulsive disorder (OCD). Given that anxiety often precedes OCD diagnosis in humans, this study investigated whether juvenile SAPAP3-KO mice exhibit anxiety-like behaviors before developing the self-grooming phenotype, and whether such behaviors respond to psilocybin treatment. The study also examined four key neuroplasticity-related synaptic proteins-GAP43, PSD95, synaptophysin, and SV2A - as SAPAP3 is a postsynaptic scaffold protein that interacts with PSD95 and may affect synaptic function.

Methods: Two studies were conducted using male and female juvenile (10-13 weeks) SAPAP3-KO mice. Study 1 compared behavioral phenotypes between homozygous (HOM), heterozygous (HET), and wild-type (WT) mice. Study 2 evaluated a different sample of HOM and WT mice and assessed the effect of psilocybin (4.4 mg/kg) on identified behavioral differences. Both studies included comprehensive behavioral testing focused on anxiety-like behavior, social interaction, and cognitive function. Additionally, levels of four synaptic proteins were measured by western blots in the frontal cortex, hippocampus, amygdala, and striatum of juvenile and adult SAPAP3-KO mice.

Results: In both studies, juvenile HOM SAPAP3-KO mice showed significant anxiety-like behaviors compared to WT mice, spending less time in open field center, and elevated plus maze open arms. They also buried fewer marbles and found fewer buried Oreos than WT mice. Psilocybin treatment did not improve these behavioral manifestations. Analysis of synaptic proteins revealed significant increases in GAP43, synaptophysin, and SV2A across multiple brain regions in adult male HOM mice and of SV2A in the frontal cortex of HOM females compared to WT, but not in juvenile mice of either sex.

Conclusions: Juvenile SAPAP3-KO mice exhibit anxiety-like behaviors before developing the characteristic excessive self-grooming phenotype, paralleling the prodromal anxiety often seen in human OCD. Unlike in adult SAPAP3-KO mice, these manifestations were not responsive to psilocybin treatment. The age-dependent increases in synaptic proteins observed in adult (but not juvenile) male SAPAP3-KO mice homozygous for the deletion and to a lesser extent in female homozygotes, may represent compensatory plasticity changes in response to the phenotype. These results provide insights into the developmental trajectory of OCD-like behaviors and associated neuroplastic adaptations.

强迫症小鼠SAPAP3模型的病前特征:行为、神经可塑性和裸盖菇素治疗。
背景:sapap3基因敲除(SAPAP3-KO)小鼠在4-6月龄时出现过度的自我梳理行为,可作为强迫症(OCD)的模型。考虑到焦虑通常先于人类的强迫症诊断,本研究调查了幼年SAPAP3-KO小鼠在发展自我梳理表型之前是否表现出焦虑样行为,以及这种行为是否对裸盖菇素治疗有反应。该研究还检测了四种关键的神经可塑性相关突触蛋白- gap43, PSD95, synaptophysin和SV2A -因为SAPAP3是一种与PSD95相互作用并可能影响突触功能的突触后支架蛋白。方法:采用雄性和雌性幼年(10-13周龄)SAPAP3-KO小鼠进行两项研究。研究1比较了纯合子(homs)、杂合子(HET)和野生型(WT)小鼠的行为表型。研究2评估了不同的HOM和WT小鼠样本,并评估了裸盖菇素(4.4 mg/kg)对确定的行为差异的影响。两项研究都包括全面的行为测试,侧重于焦虑类行为、社会互动和认知功能。此外,通过western blots检测幼年和成年SAPAP3-KO小鼠额叶皮质、海马、杏仁核和纹状体中四种突触蛋白的水平。结果:在两项研究中,幼鼠HOM SAPAP3-KO与WT小鼠相比,表现出显著的焦虑样行为,在空地中心停留的时间较少,升高+迷宫张开双臂。它们埋下的弹珠和奥利奥也比WT小鼠少。裸盖菇素治疗并没有改善这些行为表现。突触蛋白分析显示,与WT相比,成年雄性HOM小鼠的多个脑区中GAP43、synaptophysin和SV2A以及雌性HOM小鼠额叶皮层中SV2A的表达均显著增加,但在雌雄幼鼠中均没有。结论:幼年SAPAP3-KO小鼠在出现特征性的过度自我梳理表型之前表现出焦虑样行为,与人类强迫症常见的前驱焦虑相似。与成年SAPAP3-KO小鼠不同,这些表现对裸盖菇素治疗没有反应。在成年(而非幼年)雄性SAPAP3-KO小鼠纯合子中观察到突触蛋白的年龄依赖性增加,在雌性纯合子中也有较小程度的增加,这可能代表了对表型的代偿性可塑性变化。这些结果为强迫症样行为的发展轨迹和相关的神经可塑性适应提供了见解。
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来源期刊
CiteScore
8.40
自引率
2.10%
发文量
230
审稿时长
4-8 weeks
期刊介绍: The central focus of the journal is on research that advances understanding of existing and new neuropsychopharmacological agents including their mode of action and clinical application or provides insights into the biological basis of psychiatric disorders and thereby advances their pharmacological treatment. Such research may derive from the full spectrum of biological and psychological fields of inquiry encompassing classical and novel techniques in neuropsychopharmacology as well as strategies such as neuroimaging, genetics, psychoneuroendocrinology and neuropsychology.
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