An acetylcholine alpha7 positive allosteric modulator rescues a schizophrenia-associated brain endophenotype in the 15q13.3 microdeletion, encompassing CHRNA7
An acetylcholine alpha7 positive allosteric modulator rescues a schizophrenia-associated brain endophenotype in the 15q13.3 microdeletion, encompassing CHRNA7
复制标题
DOI：
10.1016/j.euroneuro.2016.03.013
复制
发表时间：
2016-07-01
影响因子：
5.6
通讯作者：
Schwarz, Adam J.
中科院分区：
文献类型：
--
作者：
Gass, Natalia;Weber-Fahr, Wolfgang;Schwarz, Adam J.
15q13.3微缺失拷贝数变异与精神分裂症和癫痫密切相关。编码烟碱乙酰胆碱α 7受体（nAChA 7 Rs）的CHRNA 7基因被假设为导致神经精神表型的主要基因之一。在这里，我们使用了最近开发的15q13.3微缺失小鼠模型，以探讨是否已建立的精神分裂症相关的连接表型在小鼠模型中复制，以及是否nAChA 7受体的阳性调节可能会使连接模式重新正常化。静息状态fMRI数据采集自携带半合子15q13.3微缺失的雄性小鼠（N=9）和野生型小鼠（N=9）。为了研究15q13.3小鼠的连接特征并测试nAChA 7正变构调节的效果，15q13.3小鼠经历两次成像，间隔一周，接受单次腹膜内注射15 mg/kg Lu AF 58801或盐水。对照组包括用盐水处理的野生型小鼠。我们进行了基于种子的功能连接分析，以描述与缺失相关的异常连接模式（15q13.3小鼠（盐水处理）与野生型小鼠（盐水处理））及其由Lu AF 58801的调节（15q13.3小鼠（Lu AF 58801处理）与15q13.3小鼠（盐水处理））。与野生型小鼠相比，15q13.3小鼠表现出主要的超连接模式。Lu AF 58801的主要作用是使前额叶和额叶、海马、纹状体、丘脑和听觉区域之间的功能连接正常化。在表达nAChA 7 Rs的大脑区域，即海马、大脑皮层和丘脑中观察到最强的作用。这些作用可能是nAChA 7 R刺激的抗癫痫、促认知和听觉门控缺陷逆转作用的基础。(C)2016 Elsevier B.V.和ECNP。All rights reserved.
The 15q13.3 microdeletion copy number variation is strongly associated with schizophrenia and epilepsy. The CHRNA7 gene, encoding nicotinic acetylcholine alpha 7 receptors (nAChA7Rs), is hypothesized to be one of the main genes in this deletion causing the neuropsychiatric phenotype. Here we used a recently developed 15q13.3 microdeletion mouse model to explore whether an established schizophrenia-associated connectivity phenotype is replicated in a murine model, and whether positive modulation of nAChA7 receptor might pharmacologically normalize the connectivity patterns. Resting-state fMRI data were acquired from male mice carrying a hemizygous 15q13.3 microdeletion (N=9) and from wild-type mice (N=9). To study the connectivity profile of 15q13.3 mice and test the effect of nAChA7 positive allosteric modulation, the 15q13.3 mice underwent two imaging sessions, one week apart, receiving a single intraperitoneal injection of either 15 mg/kg Lu AF58801 or saline. The control group comprised wild-type mice treated with saline. We performed seed-based functional connectivity analysis to delineate aberrant connectivity patterns associated with the deletion (15q13.3 mice (saline treatment) versus wild-type mice (saline treatment)) and their modulation by Lu AF58801 (15q13.3 mice (Lu AF58801 treatment) versus 15q13.3 mice (saline treatment)). Compared to wild-type mice, 15q13.3 mice evidenced a predominant hyperconnectivity pattern. The main effect of Lu AF58801 was a normalization of elevated functional connectivity between prefrontal and frontal, hippocampal, striatal, thalamic and auditory regions. The strongest effects were observed in brain regions expressing nAChA7Rs, namely hippocampus, cerebral cortex and thalamus. These effects may underlie the antiepileptic, pro cognitive and auditory gating deficit-reversal effects of nAChA7R stimulation. (C) 2016 Elsevier B.V. and ECNP. All rights reserved.