Xu Qin, Auyeung Leanne, Wang Zhangjie, Xu Yongmei, Liu Jian, Zhang Peng
Department of Neurosciences, School of Medicine, Case Western Reserve University, 2210 Circle Dr., Cleveland, OH 44106, United States.
Glycan Therapeutics Corp, 617 Hutton Street, Raleigh, NC 27606, United States.
Glycobiology. 2025 Jun 23;35(8). doi: 10.1093/glycob/cwaf039.
Excitatory and inhibitory synapses are the two major fundamental units of neuronal communication in the brain. The imbalance between excitatory and inhibitory synapses (E/I imbalance) is a leading mechanism underlying mental illness. Heparan sulfate (HS), a complex polysaccharide frequently implicated in mental disorders, is an emergent player in synaptic function. Yet, it remains unclear whether and how HS plays a preferential role in excitatory versus inhibitory synapses. This question is further complicated by the structural complexity of HS and the combined effects of both HS glycans and their attached proteoglycans. To address this challenge, we developed a platform that combines synthetic chemistry and synaptic biology to dissect the role of pure HS glycans in synapse development. As proof of principle, we assessed the effects of a synthetic dodecasaccharide (12-mer-19) and its non-sulfated counterpart (12-mer-NAc) on excitatory and inhibitory synapses in primary rat hippocampal neuron cultures. Unexpectedly, we found that 12-mer-19 selectively impaired the morphology and function of excitatory but not inhibitory synapses. Mechanistically, 12-mer-19 interferes with the interaction between neurexin1 and its partners at excitatory synapses, but has little effect on neurexin1's partner at inhibitory synapses. Moreover, 12-mer-NAc didn't have such effects, highlighting the importance of sulfated groups. Our results suggest that extracellular complex glycans may have a selective yet underappreciated role in excitatory synapses, perhaps contributing to the E/I imbalance. Moreover, current studies lay a foundation for future work to dissect the contribution of specific heparan sulfate structures to synaptic morphology and function.
兴奋性和抑制性突触是大脑中神经元通讯的两个主要基本单元。兴奋性和抑制性突触之间的失衡（E/I失衡）是精神疾病的主要潜在机制。硫酸乙酰肝素（HS）是一种经常与精神障碍有关的复合多糖，是突触功能中一个新出现的因素。然而，HS是否以及如何在兴奋性突触与抑制性突触中发挥优先作用仍不清楚。HS的结构复杂性以及HS聚糖及其附着的蛋白聚糖的综合作用使这个问题更加复杂。为了应对这一挑战，我们开发了一个结合合成化学和突触生物学的平台，以剖析纯HS聚糖在突触发育中的作用。作为原理验证，我们评估了一种合成十二糖（12-mer-19）及其非硫酸化对应物（12-mer-NAc）对原代大鼠海马神经元培养物中兴奋性和抑制性突触的影响。出乎意料的是，我们发现12-mer-19选择性地损害了兴奋性突触的形态和功能，但对抑制性突触没有影响。从机制上讲，12-mer-19干扰了神经连接蛋白1与其在兴奋性突触中的伙伴之间的相互作用，但对其在抑制性突触中的伙伴影响很小。此外，12-mer-NAc没有这种作用，突出了硫酸化基团的重要性。我们的数据表明，细胞外复合聚糖可能在兴奋性突触中具有选择性但未被充分认识的作用，这可能导致了E/I失衡。此外，目前的研究为未来剖析特定硫酸乙酰肝素结构对突触形态和功能的贡献奠定了基础。
