PDF(Pubmed)
Abstract：
Glycan alterations are associated with aging, neuropsychiatric, and neurodegenerative diseases, although the contributions of specific glycan structures to emotion and cognitive functions remain largely unknown. Here, we used a combination of chemistry and neurobiology to show that 4-O-sulfated chondroitin sulfate (CS) polysaccharides are critical regulators of perineuronal nets (PNNs) and synapse development in the mouse hippocampus, thereby affecting anxiety and cognitive abilities such as social memory. Brain-specific deletion of CS 4-O-sulfation in mice increased PNN densities in the area CA2 (cornu ammonis 2), leading to imbalanced excitatory-to-inhibitory synaptic ratios, reduced CREB activation, elevated anxiety, and social memory dysfunction. The impairments in PNN densities, CREB activity, and social memory were recapitulated by selective ablation of CS 4-O-sulfation in the CA2 region during adulthood. Notably, enzymatic pruning of the excess PNNs reduced anxiety levels and restored social memory, while chemical manipulation of CS 4-O-sulfation levels reversibly modulated PNN densities surrounding hippocampal neurons and the balance of excitatory and inhibitory synapses. These findings reveal key roles for CS 4-O-sulfation in adult brain plasticity, social memory, and anxiety regulation, and they suggest that targeting CS 4-O-sulfation may represent a strategy to address neuropsychiatric and neurodegenerative diseases associated with social cognitive dysfunction.
摘要：
聚糖改变与衰老有关，神经精神病学，和神经退行性疾病，尽管特定的聚糖结构对情绪和认知功能的贡献在很大程度上仍然未知。这里,我们使用化学和神经生物学的组合来表明，4-O-硫酸化硫酸软骨素（CS）多糖是小鼠海马中神经周网状物（PNN）和突触发育的关键调节因子，从而影响焦虑和认知能力，如社会记忆。小鼠中CS4-O-硫酸化的脑特异性缺失增加了CA2（玉米氨2）区域的PNN密度，导致兴奋性与抑制性突触比率不平衡，减少CREB激活，焦虑加剧，和社会记忆功能障碍。PNN密度的减损，CREB活动,通过在成年期对CA2区域的CS4-O-硫酸盐的选择性消融来概括社会记忆。值得注意的是,过度PNN的酶促修剪降低了焦虑水平并恢复了社会记忆，而CS4-O-硫酸化水平的化学操纵可逆地调节海马神经元周围的PNN密度以及兴奋性和抑制性突触的平衡。这些发现揭示了CS4-O-硫酸化在成人大脑可塑性中的关键作用，社会记忆,和焦虑调节，他们认为，靶向CS4-O-硫酸化可能代表解决与社会认知功能障碍相关的神经精神和神经退行性疾病的策略。
