Elevated granulocyte colony stimulating factor (CSF) causes cerebellar deficits and anxiety in a model of CSF-1 receptor related leukodystrophy

Fabrizio Biundo, Violeta Chitu, Jaafar Tindi, Nesha S. Burghardt, Gabriel G.L. Shlager, Harmony C. Ketchum, Michael A. DeTure, Dennis W. Dickson, Zbignew K. Wszolek, Kamran Khodakhah, E. Richard Stanley

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)775-794
Number of pages20
Issue number3
StatePublished - Mar 2023


  • CRL
  • CSF-1 receptor
  • G-CSF
  • HDLS
  • cerebellum
  • leukoencephalopathy
  • microglia

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience


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