1Department of Physiology and Biophysics, Biomedical Sciences Institute, University of São Paulo, Av. Prof. Lineu Prestes, 1524, São Paulo, SP 05508-000 Brazil.
2Department of Experimental Psychology, Psychology Institute, University of São Paulo, Av. Prof. Mello Moraes, 1721, São Paulo, SP 05508-030 Brazil.
Mol Autism. 2019 Apr 15;10:19. doi: 10.1186/s13229-019-0270-8. eCollection 2019.
Autism spectrum disorders (ASD) affect around 1.5% of people worldwide. Symptoms start around age 2, when children fail to maintain eye contact and to develop speech and other forms of communication. Disturbances in glutamatergic and GABAergic signaling that lead to synaptic changes and alter the balance between excitation and inhibition in the developing brain are consistently found in ASD. One of the hallmarks of these disorders is hypersensitivity to sensory stimuli; however, little is known about its underlying causes. Since the retina is the part of the CNS that converts light into a neuronal signal, we set out to study how it is affected in adolescent mice prenatally exposed to valproic acid (VPA), a useful tool to study ASD endophenotypes.
Pregnant female mice received VPA (600 mg/kg, ) or saline at gestational day 11. Their male adolescent pups (P29-35) were behaviorally tested for anxiety and social interaction. Proteins known to be related with ASD were quantified and visualized in their retinas by immunoassays, and retinal function was assessed by full-field scotopic electroretinograms (ERGs).
Early adolescent mice prenatally exposed to VPA displayed impaired social interest and increased anxiety-like behaviors consistent with an ASD phenotype. The expression of GABA, GAD, synapsin-1, and FMRP proteins were reduced in their retinas, while mGluR5 was increased. The a-wave amplitudes of VPA-exposed were smaller than those of CTR animals, whereas the b-wave and oscillatory potentials were normal.
This study establishes that adolescent male mice of the VPA-induced ASD model have alterations in retinal function and protein expression compatible with those found in several brain areas of other autism models. These results support the view that synaptic disturbances with excitatory/inhibitory imbalance early in life are associated with ASD and point to the retina as a window to understand their subjacent mechanisms.
自闭症谱系障碍（ASD）影响全球约 1.5%的人群。症状始于 2 岁左右，此时儿童无法保持眼神接触，无法发展言语和其他形式的交流。谷氨酸能和 GABA 能信号的紊乱导致突触变化，并改变发育中大脑兴奋和抑制之间的平衡，在 ASD 中始终被发现。这些疾病的标志之一是对感官刺激的过度敏感；然而，其潜在原因知之甚少。由于视网膜是将光转化为神经元信号的中枢神经系统的一部分，我们着手研究在产前暴露于丙戊酸（VPA）的青少年小鼠的视网膜如何受到影响，VPA 是研究 ASD 表型的有用工具。
妊娠雌性小鼠在妊娠第 11 天接受 VPA（600mg/kg）或生理盐水。他们的雄性青少年幼鼠（P29-35）接受焦虑和社交互动的行为测试。通过免疫测定法在视网膜中定量和可视化已知与 ASD 相关的蛋白质，并通过全视野暗视电视网膜图（ERG）评估视网膜功能。
早期青少年小鼠产前暴露于 VPA 表现出社交兴趣受损和焦虑样行为增加，与 ASD 表型一致。他们的视网膜中 GABA、GAD、突触素-1 和 FMRP 蛋白的表达减少，而 mGluR5 增加。VPA 暴露组的 a 波幅度小于对照动物，而 b 波和振荡电位正常。
本研究确立了 VPA 诱导的 ASD 模型的青少年雄性小鼠的视网膜功能和蛋白质表达发生改变，与其他自闭症模型的几个大脑区域中发现的改变一致。这些结果支持生命早期兴奋性/抑制性失衡的突触紊乱与 ASD 相关的观点，并指出视网膜是理解其潜在机制的窗口。
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