SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients.
SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients.
复制标题
DOI：
10.1038/nature12618
复制
发表时间：
2013-11-14
期刊：
影响因子：
64.8
通讯作者：
Dolmetsch RE
中科院分区：
文献类型：
--
作者：
Shcheglovitov A;Shcheglovitova O;Yazawa M;Portmann T;Shu R;Sebastiano V;Krawisz A;Froehlich W;Bernstein JA;Hallmayer JF;Dolmetsch RE
M-M综合征（PMDS）是一种复杂的神经发育障碍，其特征在于全面发育迟缓、严重言语受损、智力残疾和自闭症谱系障碍（ASD）的风险增加。PMDS由染色体22q13.3的杂合缺失引起。缺失区域中的基因是SHANK 3，其编码突触后密度（PSD）中的蛋白质。SHANK 3的罕见突变与特发性ASD、非综合征性智力残疾和精神分裂症有关。虽然SHANK 3被认为是PMDS患者神经系统异常的最可能的候选基因，但与人类神经元中该综合征相关的细胞和分子表型尚不清楚。我们从患有PMDS和自闭症的个体中产生了诱导多能干细胞（iPSC），并使用它们来产生功能性神经元。我们发现，PMDS神经元减少了Shank 3的表达和主要缺陷的兴奋性，但不是抑制性突触传递。PMDS神经元中的兴奋性突触传递可以通过恢复Shank 3表达或通过用胰岛素样生长因子1（IGF 1）处理神经元来校正。IGF 1处理促进缺乏Shank 3但含有PSD 95和NMDA受体的兴奋性突触的形成，具有快速失活动力学。我们的研究结果提供了直接的证据，在PMDS神经元的细胞兴奋和抑制的比例中断，并指出一个分子途径，可以招募恢复它。
Phelan-McDermid Syndrome (PMDS) is a complex neurodevelopmental disorder characterized by global developmental delay, severely impaired speech, intellectual disability, and an increased risk of Autism Spectrum Disorders (ASDs). PMDS is caused by heterozygous deletions of chromosome 22q13.3. Among the genes in the deleted region is SHANK3, which encodes a protein in the postsynaptic density (PSD). Rare mutations in SHANK3 have been associated with idiopathic ASDs, non-syndromic intellectual disability, and schizophrenia. Although SHANK3 is considered to be the most likely candidate gene for the neurological abnormalities in PMDS patients, the cellular and molecular phenotypes associated with this syndrome in human neurons are unknown. We generated induced pluripotent stem cells (iPSCs) from individuals with PMDS and autism and used them to produce functional neurons. We show that PMDS neurons have reduced Shank3 expression and major defects in excitatory but not inhibitory synaptic transmission. Excitatory synaptic transmission in PMDS neurons can be corrected by restoring Shank3 expression or by treating neurons with insulin-like growth factor 1 (IGF1). IGF1 treatment promotes formation of excitatory synapses that lack Shank3 but contain PSD95 and NMDA receptors with fast deactivation kinetics. Our findings provide direct evidence for a disruption in the ratio of cellular excitation and inhibition in PMDS neurons, and point to a molecular pathway that can be recruited to restore it.
登录
查看更多内容
影响因子：
30.8
作者：
Durand, Christelle M.;Betancur, Catalina;Bourgeron, Thomas
通讯作者：
Bourgeron, Thomas
影响因子：
6.2
作者：
Bozdagi O;Sakurai T;Papapetrou D;Wang X;Dickstein DL;Takahashi N;Kajiwara Y;Yang M;Katz AM;Scattoni ML;Harris MJ;Saxena R;Silverman JL;Crawley JN;Zhou Q;Hof PR;Buxbaum JD
通讯作者：
Buxbaum JD
DOI：
10.1523/jneurosci.0097-09.2009
发表时间：
2009-06-24
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Akhtar MW;Raingo J;Nelson ED;Montgomery RL;Olson EN;Kavalali ET;Monteggia LM
通讯作者：
Monteggia LM
影响因子：
5.2
作者：
Boccuto, Luigi;Lauri, Maria;Schwartz, Charles E.
通讯作者：
Schwartz, Charles E.
影响因子：
16.2
作者：
Goold, Carleton P.;Nicoll, Roger A.
通讯作者：
Nicoll, Roger A.