种系和成体PV+神经元聚集蛋白敲除对神经元周围网络和PV+神经元功能的差异影响

IF 9.6 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Sverre Grødem, Elise Holter Thompson, Malin Benum Røe, Guro Helen Vatne, Ingeborg Nymoen Nystuen, Alessio Buccino, Tarjei Otterstad, Torkel Hafting, Marianne Fyhn, Kristian Kinden Lensjø
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引用次数: 0

摘要

神经周围网(PNNs)是细胞外基质的浓缩形式,主要存在于表达小蛋白(PV+)的中间神经元周围。出生后PV+神经元的成熟伴随着pnn的形成和可塑性的降低。PNN和PV+神经元功能的改变已被描述为精神障碍,如精神分裂症和自闭症。pnn的形成高度依赖于聚合蛋白,这是一种由ACAN基因编码的蛋白多糖,但它是否由PV+神经元自身产生尚不清楚。因此,我们建立了敲除(KO)小鼠模型(ACANflx/PVcre)和腺相关病毒,分别在种系动物和成年动物中特异性地消除PV+神经元的聚集蛋白产生。种系KO (ACANflx/PVcre)消除了Wisteria floribunda凝集素(WFA)标记的PNN的表达,WFA是最常用的PNN标志物。令人惊讶的是,成年ACANflx/PVcre小鼠PV+中间神经元的电生理特性和眼优势可塑性与对照组相似。相比之下,aav介导的ACAN敲除在成年小鼠中增加了眼优势可塑性。此外,KO小鼠体内软骨素酶ABC处理导致PV+细胞放电率降低,自发兴奋性突触后电流(sEPSC)频率增加,这是一种与WT动物chABC处理相关的表型。这些发现表明,补偿机制可能在发育过程中被激活,以响应种系聚集蛋白的丢失。事实上,大块组织的qPCR表明,其他PNN成分,包括neurocan和tenascin-R,在KO动物中表达水平较高。最后,行为测试显示,在Morris水迷宫中,ACANflx/PVcre小鼠具有与对照组相似的长期记忆。然而,在空间学习过程中,他们采用了更大胆的搜索策略,在开阔场地和零迷宫中表现出较低的焦虑相关行为。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Differential impacts of germline and adult aggrecan knockout in PV+ neurons on perineuronal nets and PV+ neuronal function

Differential impacts of germline and adult aggrecan knockout in PV+ neurons on perineuronal nets and PV+ neuronal function

Perineuronal nets (PNNs) are a condensed form of extracellular matrix primarily found around parvalbumin-expressing (PV+) interneurons. The postnatal maturation of PV+ neurons is accompanied with the formation of PNNs and reduced plasticity. Alterations in PNN and PV+ neuron function have been described for mental disorders such as schizophrenia and autism. The formation of PNNs is highly dependent on aggrecan, a proteoglycan encoded by the ACAN gene, but it remains unknown if it is produced by the PV+ neurons themselves. Thus, we established a knockout (KO) mouse model (ACANflx/PVcre) and an adeno-associated virus to specifically eliminate aggrecan production from PV+ neurons, in the germline or adult animals, respectively. The germline KO (ACANflx/PVcre) eliminated the expression of PNNs labeled by Wisteria floribunda agglutinin (WFA), the most commonly used PNN marker. Surprisingly, electrophysiological properties of PV+ interneurons and ocular dominance plasticity of adult ACANflx/PVcre mice were similar to controls. In contrast, AAV-mediated ACAN knockout in adult mice increased ocular dominance plasticity. Moreover, in vivo Chondroitinase ABC treatment of KO mice resulted in reduced firing rate of PV+ cells and increased frequency of spontaneous excitatory postsynaptic currents (sEPSC), a phenotype associated with chABC treatment of WT animals. These findings suggest that compensatory mechanisms may be activated during development in response to the germline loss of aggrecan. Indeed, qPCR of bulk tissue indicates that other PNN components, including neurocan and tenascin-R, are expressed at higher levels in the KO animals. Finally, behavioral testing revealed that ACANflx/PVcre mice had similar long-term memory as controls in the Morris water maze. However, they employed bolder search strategies during spatial learning and showed lower level of anxiety-related behavior in an open field and zero maze.

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来源期刊
Molecular Psychiatry
Molecular Psychiatry 医学-精神病学
CiteScore
20.50
自引率
4.50%
发文量
459
审稿时长
4-8 weeks
期刊介绍: Molecular Psychiatry focuses on publishing research that aims to uncover the biological mechanisms behind psychiatric disorders and their treatment. The journal emphasizes studies that bridge pre-clinical and clinical research, covering cellular, molecular, integrative, clinical, imaging, and psychopharmacology levels.
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