Testing the excitation/inhibition imbalance hypothesis in a mouse model of the autism spectrum disorder: in vivo neurospectroscopy and molecular evidence for regional phenotypes.
Testing the excitation/inhibition imbalance hypothesis in a mouse model of the autism spectrum disorder: in vivo neurospectroscopy and molecular evidence for regional phenotypes.
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DOI：
10.1186/s13229-017-0166-4
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发表时间：
2017
期刊：
影响因子：
6.2
通讯作者：
Castelo-Branco M
中科院分区：
文献类型：
--
作者：
Gonçalves J;Violante IR;Sereno J;Leitão RA;Cai Y;Abrunhosa A;Silva AP;Silva AJ;Castelo-Branco M
兴奋/抑制(E/I)失衡仍然是自闭症谱系障碍(ASD)中一个被广泛讨论的假说。这种失衡的存在可能潜在地定义了与这种病理相关的认知障碍的治疗目标。因此，对与自闭症相关的单基因疾病的研究，如1型神经纤维瘤病(NF1)，代表了一种分离ASD相关认知障碍潜在机制的有希望的方法。然而，NF1小鼠模型显示γ-氨基丁酸(GABA)神经传递增加，而人类疾病显示皮质GABA水平降低。因此，澄清E/I失衡假说是否成立是很重要的。我们假设E/I可能依赖于不同的突触前和突触后的推拉机制，这种机制可能是区域依赖的。在目前的研究中，我们评估了E/I调节的两个关键组成部分：神经递质浓度和GABA(A)受体水平。在这种与ASD相关的动物模型NF1+/−小鼠中，通过体内磁共振波谱(MRS)和分子方法相结合的方法，对海马区、纹状体和前额叶皮质进行了测量。皮质和纹状体GABA/谷氨酸比值升高。在突触后水平，在海马区发现了非常高的GABA(A)受体的表达，与GABA水平的小幅下降不成比例。因此，GABA能张力(无论是通过受体水平的变化还是通过GABA/谷氨酸比率)似乎在所有区域都得到了增强，尽管机制不同。我们的数据支持NF1中E/I失衡的假说，同时表明突触前和突触后的变化是区域特有的。所有这些发现与我们之前发现的抑制音增加的生理学证据是一致的。这种异质性表明，解决ASD神经化学失衡的治疗方法可能需要专注于可以找到收敛生理机制的靶点。
Excitation/inhibition (E/I) imbalance remains a widely discussed hypothesis in autism spectrum disorders (ASD). The presence of such an imbalance may potentially define a therapeutic target for the treatment of cognitive disabilities related to this pathology. Consequently, the study of monogenic disorders related to autism, such as neurofibromatosis type 1 (NF1), represents a promising approach to isolate mechanisms underlying ASD-related cognitive disabilities. However, the NF1 mouse model showed increased γ-aminobutyric acid (GABA) neurotransmission, whereas the human disease showed reduced cortical GABA levels. It is therefore important to clarify whether the E/I imbalance hypothesis holds true. We hypothesize that E/I may depend on distinct pre- and postsynaptic push-pull mechanisms that might be are region-dependent. In current study, we assessed two critical components of E/I regulation: the concentration of neurotransmitters and levels of GABA(A) receptors. Measurements were performed across the hippocampi, striatum, and prefrontal cortices by combined in vivo magnetic resonance spectroscopy (MRS) and molecular approaches in this ASD-related animal model, the Nf1 +/− mouse. Cortical and striatal GABA/glutamate ratios were increased. At the postsynaptic level, very high receptor GABA(A) receptor expression was found in hippocampus, disproportionately to the small reduction in GABA levels. Gabaergic tone (either by receptor levels change or GABA/glutamate ratios) seemed therefore to be enhanced in all regions, although by a different mechanism. Our data provides support for the hypothesis of E/I imbalance in NF1 while showing that pre- and postsynaptic changes are region-specific. All these findings are consistent with our previous physiological evidence of increased inhibitory tone. Such heterogeneity suggests that therapeutic approaches to address neurochemical imbalance in ASD may need to focus on targets where convergent physiological mechanisms can be found.
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影响因子：
10.6
作者：
Foss-Feig JH;Adkinson BD;Ji JL;Yang G;Srihari VH;McPartland JC;Krystal JH;Murray JD;Anticevic A
通讯作者：
Anticevic A
影响因子：
4.7
作者：
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通讯作者：
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影响因子：
64.5
作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
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