CSF1R-related leukoencephalopathy: experimental models and potential for treatment.

Dominant and recessive mutations in the human CSF1R gene are associated with microglial deficiency in the brain and severe neurodegenerative disease, known as CSF1R-related leukoencephalopathy (CRL). Dominant and recessive Csf1r mutations have been generated in mice, rats, zebrafish and chicken, providing models of the complete or partial microglial loss seen in patients. The impact of Csf1r mutations in inbred mice depends upon genetic background. For example, Csf1r mutants in the C57BL/6J strain are uniquely susceptible to perinatal mortality and hydrocephalus. Congenital microglial deficiency in a range of animal models does not influence postnatal brain development but is associated with age-dependent neuropathology that resembles CRL, indicating that microglial deficiency contributes to disease. None of the available models fully recapitulates the severe functional motor and cognitive impairments seen in patients, raising questions about species differences and the relative contributions of genetic and environmental modifiers. However, they have provided platforms to test ways to repopulate the brain with functional microglia. Here, we briefly review the genetic basis for CRL and evidence of variable penetrance. We also assess experimental models that can enable the development of therapeutic strategies.