Autism-like socio-communicative deficits and stereotypies in mice lacking heparan sulfate
Autism-like socio-communicative deficits and stereotypies in mice lacking heparan sulfate
复制标题
DOI：
10.1073/pnas.1117881109
复制
发表时间：
2012-03-27
影响因子：
11.1
通讯作者：
Yamaguchi, Yu
中科院分区：
文献类型：
--
作者：
Irie, Fumitoshi;Badie-Mahdavi, Hedieh;Yamaguchi, Yu
硫酸乙酰肝素调节多种细胞表面信号事件，其在神经系统发育中的作用最近已经越来越多地通过使用携带编码其合成酶的基因突变的遗传模型的研究发现。另一方面，尽管有一些证据表明硫酸肝素在突触功能调节中的作用，但对其在成人大脑生理功能中的作用却知之甚少。为了解决这个问题，我们通过有条件地灭活Ext1来消除出生后神经元中的硫酸肝素，Ext1是一种编码硫酸肝素合成所必需的酶的基因。由此产生的条件突变小鼠在大脑细胞结构中没有可检测到的形态学缺陷。值得注意的是，这些突变小鼠几乎重现了所有自闭症症状，包括社交障碍、刻板印象表达、重复行为、超声波发声障碍以及一些相关特征。通过c-Fos免疫组织化学绘制的神经元激活图谱表明，这些小鼠杏仁核中对社交刺激的神经元激活减弱。杏仁核锥体神经元的电生理表现出兴奋性突触传递的衰减，可能是由于突触定位的ampa型谷氨酸受体水平的降低。我们的研究结果表明，硫酸肝素对谷氨酸突触的正常功能至关重要，其缺乏介导了自闭症的社会交际缺陷和刻板印象特征。
Heparan sulfate regulates diverse cell-surface signaling events, and its roles in the development of the nervous system recently have been increasingly uncovered by studies using genetic models carrying mutations of genes encoding enzymes for its synthesis. On the other hand, the role of heparan sulfate in the physiological function of the adult brain has been poorly characterized, despite several pieces of evidence suggesting its role in the regulation of synaptic function. To address this issue, we eliminated heparan sulfate from postnatal neurons by conditionally inactivating Ext1, the gene encoding an enzyme essential for heparan sulfate synthesis. Resultant conditional mutant mice show no detectable morphological defects in the cytoarchitecture of the brain. Remarkably, these mutant mice recapitulate almost the full range of autistic symptoms, including impairments in social interaction, expression of stereotyped, repetitive behavior, and impairments in ultrasonic vocalization, as well as some associated features. Mapping of neuronal activation by c-Fos immunohistochemistry demonstrates that neuronal activation in response to social stimulation is attenuated in the amygdala in these mice. Electrophysiology in amygdala pyramidal neurons shows an attenuation of excitatory synaptic transmission, presumably because of the reduction in the level of synaptically localized AMPA-type glutamate receptors. Our results demonstrate that heparan sulfate is critical for normal functioning of glutamatergic synapses and that its deficiency mediates socio-communicative deficits and stereotypies characteristic for autism.