Heparan sulfate (HS) is a linear polysaccharide that plays a key role in cellular signaling networks. HS functions are regulated by its 6-O-sulfation, which is catalyzed by three HS 6-O-sulfotransferases (HS6STs). Notably, HS6ST2 is mainly expressed in the brain and HS6ST2 mutations are linked to brain disorders, but the underlying mechanisms remain poorly understood. To determine the role of Hs6st2 in the brain, we carried out a series of molecular and behavioral assessments on Hs6st2 knockout mice. We first carried out strong anion exchange-high performance liquid chromatography and found that knockout of Hs6st2 moderately decreases HS 6-O-sulfation levels in the brain. We then assessed body weights and found that Hs6st2 knockout mice exhibit increased body weight, which is associated with abnormal metabolic pathways. We also performed behavioral tests and found that Hs6st2 knockout mice showed memory deficits, which recapitulate patient clinical symptoms. To determine the molecular mechanisms underlying the memory deficits, we used RNA sequencing to examine transcriptomes in two memory-related brain regions, the hippocampus and cerebral cortex. We found that knockout of Hs6st2 impairs transcriptome in the hippocampus, but only mildly in the cerebral cortex. Furthermore, the transcriptome changes in the hippocampus are enriched in dendrite and synapse pathways. We also found that knockout of Hs6st2 decreases HS levels and impairs dendritic spines in hippocampal CA1 pyramidal neurons. Taken together, our study provides novel molecular and behavioral insights into the role of Hs6st2 in the brain, which facilitates a better understanding of HS6ST2 and HS-linked brain disorders.

中文翻译：

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敲除小鼠中智力障碍相关基因 Hs6st2 会降低硫酸乙酰肝素 6-O-硫酸化，损害海马神经元的树突棘，并影响记忆。

硫酸乙酰肝素 (HS) 是一种线性多糖，在细胞信号网络中发挥关键作用。HS 功能由其 6-O-硫酸化调节，而 6-O-硫酸化由三种 HS 6-O-磺基转移酶 (HS6ST) 催化。值得注意的是，HS6ST2 主要在大脑中表达，HS6ST2 突变与大脑疾病有关，但其潜在机制仍知之甚少。为了确定 Hs6st2 在大脑中的作用，我们对 Hs6st2 敲除小鼠进行了一系列分子和行为评估。我们首先进行了强阴离子交换-高效液相色谱分析，发现敲除Hs6st2可适度降低大脑中的HS 6-O-硫酸化水平。然后我们评估了体重，发现 Hs6st2 敲除小鼠体重增加，这与代谢途径异常有关。我们还进行了行为测试，发现 Hs6st2 敲除小鼠表现出记忆缺陷，这再现了患者的临床症状。为了确定记忆缺陷背后的分子机制，我们使用 RNA 测序来检查两个与记忆相关的大脑区域（海马体和大脑皮层）的转录组。我们发现 Hs6st2 的敲除会损害海马体的转录组，但对大脑皮层的转录组影响轻微。此外，海马体中的转录组变化在树突和突触通路中丰富。我们还发现，敲除 Hs6st2 会降低 HS 水平并损害海马 CA1 锥体神经元的树突棘。总而言之，我们的研究为 Hs6st2 在大脑中的作用提供了新的分子和行为见解，这有助于更好地了解 HS6ST2 和 HS 相关的大脑疾病。