Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada.
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada; Department of Biomedical Engineering, McGill University, Montreal, Quebec, Canada.
Neuroscience. 2021 Jun 15;465:128-141. doi: 10.1016/j.neuroscience.2021.04.023. Epub 2021 May 2.
The Small Optic Lobe (SOL) family of calpains are intracellular cysteine proteases that are expressed in the nervous system and play an important role in neuronal development in both Drosophila, where loss of this calpain leads to the eponymous small optic lobes, and in mouse and human, where loss of this calpain leads to eye anomalies. Some human individuals with biallelic variants in CAPN15 also have developmental delay and autism. However, neither the specific effect of the loss of the Capn15 protein on brain development nor the brain regions where this calpain is expressed in the adult is known. Here we show using small animal MRI that mice with the complete loss of Capn15 have smaller brains overall with larger decreases in the thalamus and subregions of the hippocampus. These losses are not seen in Capn15 conditional knockout (KO) mice where Capn15 is knocked out only in excitatory neurons in the adult. Based on β-galactosidase expression in an insert strain where lacZ is expressed under the control of the Capn15 promoter, we show that Capn15 is expressed in adult mice, particularly in neurons involved in plasticity such as the hippocampus, lateral amygdala and Purkinje neurons, and partially in other non-characterized cell types. The regions of the brain in the adult where Capn15 is expressed do not correspond well to the regions of the brain most affected by the complete knockout suggesting distinct roles of Capn15 in brain development and adult brain function.
小脑脑片（SOL）家族的钙蛋白酶是细胞内半胱氨酸蛋白酶，在神经系统中表达，在果蝇的神经元发育中发挥重要作用，这种钙蛋白酶的缺失会导致小视神经，在人和小鼠中，这种钙蛋白酶的缺失会导致眼睛异常。一些人类个体的 CAPN15 存在双等位基因突变，也存在发育迟缓和自闭症。然而，Capn15 蛋白缺失对大脑发育的具体影响，以及这种钙蛋白酶在成年期在大脑中表达的区域都不清楚。在这里，我们使用小动物 MRI 显示，Capn15 完全缺失的小鼠大脑总体较小，丘脑和海马亚区的减少更为明显。这些缺失在 Capn15 条件性敲除（KO）小鼠中没有出现，在成年时 Capn15 只在兴奋性神经元中被敲除。基于在插入品系中β-半乳糖苷酶的表达，在 Capn15 启动子的控制下，lacZ 表达，我们表明 Capn15 在成年小鼠中表达，特别是在涉及可塑性的神经元中，如海马、外侧杏仁核和浦肯野细胞，并部分在其他未被鉴定的细胞类型中表达。成年期大脑中 Capn15 表达的区域与完全敲除影响最大的大脑区域不太吻合，这表明 Capn15 在大脑发育和成年期大脑功能中具有不同的作用。
