The human 15q13.3 microdeletion syndrome (DS) is caused by a heterozygous microdeletion (MD) affecting six genes: FAN1; MTMR10; TRPM1; KLF13; OTUD7A; and CHRNA7. Carriers are at risk for intellectual disability, epilepsy, autism spectrum disorder, and schizophrenia. Here we used the Df[h15q13]/+ mouse model with an orthologous deletion to further characterize molecular, neurophysiological, and behavioral parameters that are relevant to the 15q13.3 DS. First, we verified the expression and distribution of the α7 nicotinic acetylcholine receptor (nAChR), a gene product of the CHRNA7, in cortical and subcortical areas. Results revealed similar mRNA distribution pattern in wildtype (WT) and heterozygous (Het) mice, with about half the number of α7 nAChR binding sites in mutants. Hippocampal recordings showed similar input/output responses of field excitatory post-synaptic potentials and theta-burst induced long-term potentiation in WT and Het mice. Het males exhibited impaired spatial learning acquisition in the Barnes Maze. Indicative of increased seizure susceptibility, Het mice developed secondary seizures after 6-Hz corneal stimulation, and had significantly increased sensitivity to the chemoconvulsant pentylenetetrazol resulting in increased spiking in hippocampal EEG recordings. Basal mRNA expression of brain derived neurotrophic factor and activity regulated immediate early genes (c-fos, Arc, Erg-1 and Npas4) during adolescence, a critical period of brain maturation, was unaffected by genotype. Thus, the MD did not show gross neuroanatomical, molecular, and neurophysiological abnormalities despite deficits in spatial learning and increased susceptibility to seizures. Altogether, our results verify the phenotypic profile of the heterozygous Df[h15q13]/+ mouse model and underscore its translational relevance for human 15q13.3 DS.

人类 15q13.3 微缺失综合征 (DS) 是由影响六个基因的杂合微缺失 (MD) 引起的：FAN1；MTMR10；TRPM1; KLF13; OTUD7A; 和 CHRNA7。携带者有患智力障碍、癫痫、自闭症谱系障碍和精神分裂症的风险。在这里，我们使用具有直系同源缺失的 Df[h15q13]/+ 小鼠模型来进一步表征与 15q13.3 DS 相关的分子、神经生理学和行为参数。首先，我们验证了 α7 烟碱乙酰胆碱受体 (nAChR)（CHRNA7 的基因产物）在皮质和皮质下区域的表达和分布。结果显示野生型 (WT) 和杂合 (Het) 小鼠的 mRNA 分布模式相似，突变体中 α7 nAChR 结合位点的数量约为一半。海马记录显示，在 WT 和 Het 小鼠中，场兴奋性突触后电位和 theta-burst 诱导的长期增强的输入/输出反应相似。Het 雄性在巴恩斯迷宫中表现出受损的空间学习习得。Het 小鼠在 6 赫兹角膜刺激后出现继发性癫痫，并且对化学惊厥剂戊四唑的敏感性显着增加，导致海马脑电图记录中的峰值增加，这表明癫痫易感性增加。脑源性神经营养因子的基础 mRNA 表达和活动在青春期（大脑成熟的关键时期）调节即刻早期基因（c-fos、Arc、Erg-1 和 Npas4）不受基因型的影响。因此，MD 没有显示大体神经解剖学、分子学、尽管空间学习缺陷和癫痫发作的易感性增加，但神经生理学异常。总之，我们的结果验证了杂合 Df[h15q13]/+ 小鼠模型的表型特征，并强调了其与人类 15q13.3 DS 的翻译相关性。