Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, USA.
The Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, USA.
Glia. 2023 Mar;71(3):775-794. doi: 10.1002/glia.24310. Epub 2022 Nov 26.
Colony stimulating factor (CSF) receptor-1 (CSF-1R)-related leukoencephalopathy (CRL) is an adult-onset, demyelinating and neurodegenerative disease caused by autosomal dominant mutations in CSF1R, modeled by the Csf1r mouse. The expression of Csf2, encoding granulocyte-macrophage CSF (GM-CSF) and of Csf3, encoding granulocyte CSF (G-CSF), are elevated in both mouse and human CRL brains. While monoallelic targeting of Csf2 has been shown to attenuate many behavioral and histological deficits of Csf1r mice, including cognitive dysfunction and demyelination, the contribution of Csf3 has not been explored. In the present study, we investigate the behavioral, electrophysiological and histopathological phenotypes of Csf1r mice following monoallelic targeting of Csf3. We show that Csf3 heterozygosity normalized the Csf3 levels in Csf1r mouse brains and ameliorated anxiety-like behavior, motor coordination and social interaction deficits, but not the cognitive impairment of Csf1r mice. Csf3 heterozygosity failed to prevent callosal demyelination. However, consistent with its effects on behavior, Csf3 heterozygosity normalized microglial morphology in the cerebellum and in the ventral, but not in the dorsal hippocampus. Csf1r mice exhibited altered firing activity in the deep cerebellar nuclei (DCN) associated with increased engulfment of glutamatergic synapses by DCN microglia and increased deposition of the complement factor C1q on glutamatergic synapses. These phenotypes were significantly ameliorated by monoallelic deletion of Csf3. Our current and earlier findings indicate that G-CSF and GM-CSF play largely non-overlapping roles in CRL-like disease development in Csf1r mice.
集落刺激因子 (CSF) 受体-1 (CSF-1R) 相关的脑白质病 (CRL) 是一种由 CSF1R 上的常染色体显性突变引起的成年发病、脱髓鞘和神经退行性疾病，由 Csf1r 小鼠建模。在 CRL 小鼠和人类大脑中，编码粒细胞-巨噬细胞 CSF (GM-CSF) 的 Csf2 和编码粒细胞 CSF (G-CSF) 的 Csf3 的表达均升高。虽然已经证明单等位基因靶向 Csf2 可减轻 Csf1r 小鼠的许多行为和组织学缺陷，包括认知功能障碍和脱髓鞘，但 Csf3 的贡献尚未得到探索。在本研究中，我们研究了单等位基因靶向 Csf3 后 Csf1r 小鼠的行为、电生理和组织病理学表型。我们表明，Csf3 杂合性使 Csf1r 小鼠大脑中的 Csf3 水平正常化，并改善了焦虑样行为、运动协调和社交互动缺陷，但不能改善 Csf1r 小鼠的认知障碍。Csf3 杂合性未能预防胼胝体脱髓鞘。然而，与它对行为的影响一致，Csf3 杂合性使小脑和腹侧但不是背侧海马中的小胶质细胞形态正常化。Csf1r 小鼠在深部小脑核 (DCN) 中表现出改变的放电活动，与 DCN 小胶质细胞吞噬谷氨酸能突触增多以及补体因子 C1q 在谷氨酸能突触上沉积增加有关。这些表型通过单等位基因缺失 Csf3 得到显著改善。我们目前和早期的研究结果表明，G-CSF 和 GM-CSF 在 Csf1r 小鼠 CRL 样疾病发展中发挥着很大程度上非重叠的作用。
