Autism Spectrum Disorders (ASDs) are neurodevelopmental disorders characterised by deficits in social interactions and repetitive behaviours. ASDs have a strong genetic basis with mutations involved in the development and function of neural circuitry. Shank proteins act as master regulators of excitatory glutamatergic synapses, and Shank mutations have been identified in people with ASD. Here, we have investigated the impact of ASD-associated Shank2 single nucleotide variants (SNVs) at the synaptic level, and the potential of in vitro zinc supplementation to prevent synaptic deficits. Dissociated rat hippocampal cultures expressing enhanced green fluorescent protein (EGFP) tagged Shank2-Wildtype (WT), and ASD-associated Shank2 single nucleotide variants (SNVs: S557N, V717F, and L1722P), were cultured in the absence or presence of 10 μM zinc. In comparison to Shank2-WT, ASD-associated Shank2 SNVs induced significant decreases in synaptic density and reduced the frequency of miniature excitatory postsynaptic currents. These structural and functional ASD-associated synaptic deficits were prevented by chronic zinc supplementation and further support zinc supplementation as a therapeutic target in ASD.

中文翻译：

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体外补锌改变自闭症谱系障碍相关的海马神经元Shank2点突变引起的突触缺陷

自闭症谱系障碍 (ASD) 是一种神经发育障碍，其特征是社交互动和重复行为的缺陷。自闭症谱系障碍具有很强的遗传基础，其突变涉及神经回路的发育和功能。Shank 蛋白充当兴奋性谷氨酸能突触的主要调节因子，并且在 ASD 患者中发现了 Shank 突变。在这里，我们研究了 ASD 相关 Shank2 单核苷酸变异 (SNV) 在突触水平的影响，以及体外补锌预防突触缺陷的潜力。在不存在或存在 10 μM 锌的情况下培养表达增强型绿色荧光蛋白 (EGFP) 标记的 Shank2-Wildtype (WT) 和 ASD 相关 Shank2 单核苷酸变体（SNV：S557N、V717F 和 L1722P）的离解大鼠海马培养物. 与 Shank2-WT 相比，ASD 相关的 Shank2 SNV 诱导突触密度显着降低并降低微型兴奋性突触后电流的频率。这些结构性和功能性 ASD 相关的突触缺陷可以通过长期补锌来预防，并进一步支持补锌作为 ASD 的治疗靶点。