Abnormal mGluR-mediated synaptic plasticity and autism-like behaviours in Gprasp2 mutant mice
Abnormal mGluR-mediated synaptic plasticity and autism-like behaviours in Gprasp2 mutant mice
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DOI：
10.1038/s41467-019-09382-9
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发表时间：
2019-03-29
影响因子：
16.6
通讯作者：
Peca, Joao
中科院分区：
文献类型：
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作者：
Edfawy, Mohamed;Guedes, Joana R.;Peca, Joao
自闭症谱系障碍 (ASD) 的特点是社交互动功能障碍、刻板行为以及智力障碍的高并发症。多种综合征性和非综合征性神经发育障碍与代谢型谷氨酸受体 (mGluR) 信号传导的改变有关。这些受体有助于突触可塑性、脊柱成熟和神经回路发育。在这里，我们研究了 Gprasp2 的生理作用，该基因与神经发育障碍有关，并参与 G 蛋白偶联受体的内吞后分选。我们发现 Gprasp2 缺失会导致小鼠出现类似 ASD 的行为以及突触通讯的改变。操纵 Gprasp2 的水平可以双向调节 mGluR(5) 的表面可用性，并产生树突复杂性、树突棘密度和突触成熟的改变。 Gprasp2 的缺失会导致海马长期抑郁增强，这与 mGluR 依赖性激活的促进一致。这些发现证明了 Gprasp2 在谷氨酸能突触中的作用，并提出了该基因与神经发育疾病相关的可能机制。
Autism spectrum disorder (ASD) is characterized by dysfunction in social interactions, stereotypical behaviours and high co-morbidity with intellectual disability. A variety of syndromic and non-syndromic neurodevelopmental disorders have been connected to alterations in metabotropic glutamate receptor (mGluR) signalling. These receptors contribute to synaptic plasticity, spine maturation and circuit development. Here, we investigate the physiological role of Gprasp2, a gene linked to neurodevelopmental disabilities and involved in the postendocytic sorting of G-protein-coupled receptors. We show that Gprasp2 deletion leads to ASD-like behaviour in mice and alterations in synaptic communication. Manipulating the levels of Gprasp2 bidirectionally modulates the surface availability of mGluR(5) and produces alterations in dendritic complexity, spine density and synaptic maturation. Loss of Gprasp2 leads to enhanced hippocampal long-term depression, consistent with facilitated mGluR-dependent activation. These findings demonstrate a role for Gprasp2 in glutamatergic synapses and suggest a possible mechanism by which this gene is linked to neurodevelopmental diseases.