Enzymatic Digestion of Hyaluronan-Based Brain Extracellular Matrix in vivo Can Induce Seizures in Neonatal Mice
Enzymatic Digestion of Hyaluronan-Based Brain Extracellular Matrix in vivo Can Induce Seizures in Neonatal Mice
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DOI：
10.3389/fnins.2019.01033
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发表时间：
2019-09-26
影响因子：
4.3
通讯作者：
Mukhina, Irina
中科院分区：
文献类型：
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作者：
Balashova, Alena;Pershini, Vladimir;Mukhina, Irina
透明质酸（HA）作为脑细胞外基质（ECM）的一种成分，在神经系统中发挥着重要作用，并参与血管性认知障碍和痴呆的突触可塑性改变。HA分解是中风损伤急性期的特征，并且可能通过增强炎症反应而有害。最近的研究表明，缺乏透明质酸合成酶的基因敲除小鼠在体内表现出癫痫表型，并且去除HA导致体外培养的海马神经元中癫痫样活动的延迟发展。在这里，我们研究了在出生后早期海马中透明质酸的消化是否会引发癫痫发作。使用立体定位方法将透明质酸酶（Hyal）（5 U/ul）双侧注射到C57 BL/6 j小鼠（P17）海马CA 1区，以去除基于透明质酸的ECM。酶消化基于透明质酸的脑ECM后2小时海马组织的转录组分析显示，与媒介物组相比，参与炎症反应（TLR 2、CCL 2、3、5）、神经炎症、轴突导向和肝配蛋白受体信号传导的蛋白质的基因表达增加。注射透明质酸酶的小鼠在注射后72 h表现出延迟的听源性癫痫发作和工作记忆的改善，而由于旷场测试，自发活动、焦虑水平和探索行为没有变化。所获得的结果表明，在新生儿期，通过酶消化基于透明质酸的脑ECM激活神经炎症与其随后对癫痫发作的反应性之间存在联系，这可能在发育中的大脑的功能特征中发挥重要作用，包括其癫痫发作倾向。
It is well-known that hyaluronic acid (HA) as a component of brain extracellular matrix (ECM) plays a pivotal role in the nervous system and is involved in synaptic plasticity changes in vascular cognitive impairment and dementia. HA breakdown is a feature of the acute stage of stroke injury and may be detrimental through enhancement of the inflammatory response. Recent studies have shown that knockout mice lacking hyaluronic acid synthetase demonstrates epileptic phenotype in vivo and removal of HA leads to delayed development of epileptiform activity in cultured hippocampal neurons in vitro. Here, we studied whether digestion of hyaluronic acid in the hippocampus in early postnatal period can trigger seizures. Hyaluronidase (Hyal) (5 U/mu l) was bilaterally injected into C57BL/6j mice (P17) CA1 field of hippocampus using the stereotaxic method to remove hyaluronan-based ECM. Transcriptome analysis of hippocampal tissue 2 h after enzymatic digestion of hyaluronan-based brain ECM revealed increased gene expression of proteins involved in inflammation reactions (TLR2, CCL2,3,5), neuroinflammation, axonal guidance and ephrin receptor signaling, versus the vehicle group. Mice injected with hyaluronidase exhibited delayed audiogenic seizures and improvement in working memory 72 h after injection, while there were no changes in locomotor activity, anxious level and exploratory behavior due to the open field test. The obtained results point to a link between the activation of neuroinflammation by enzymatic digestion of hyaluronan-based brain ECM during the neonatal period and their subsequent reactivity to seizures, which may play an important role in the functional features of the developing brain, including its seizure propensity.