THE HEMATOPOIETIC CYTOKINE, COLONY-STIMULATING FACTOR-1, IS ALSO A GROWTH-FACTOR IN THE CNS - CONGENITAL ABSENCE OF CSF-1 IN MICE RESULTS IN ABNORMAL MICROGLIAL RESPONSE AND INCREASED NEURON VULNERABILITY TO INJURY

In this study we used op/op mice, which are deficient in the hematopoi etic cytokine, colony-stimulating factor 1 (CSF-1), to determine the e ffect of CSF-1 on neuronal survival and microglial response in injury. In normal mice microglia express the CSF-1 receptor and are primarily regulated by CSF-1, produced mainly by astrocytes. The CSF-1 deficien cy in op/op mice results in a depletion in the number of monocytes and macrophages but does not affect the number or morphology of microglia . We produced an ischemic lesion in the cerebral cortex of mice by dis rupting the pia-arachnoid blood vessels in a defined area. Using Nissl stain and astrocyte- and microglia-specific antibodies, we determined the number of viable neurons in such injury and the intensity of glia l reaction. The cellular response to injury on the operated side of op /op mice was compared to that on the non-operated contralateral side a nd to the cellular response in similar lesions in CSF-1 producing C3H/ HeJ mice. We found that the systemic lack of CSF-1 in op/op mice resul ts in a significant increase in neuron vulnerability to ischemic injur y and considerably reduced microglial response to neuron injury. Remed ying the CSF-1 deficiency, either by grafting CSF-1 secreting astrogli a into the brain or by implanting encapsulated CSF-1 secreting fibrobl ast-like cells into the peritoneum, partially restores the microglial response to neuron injury and significantly potentiates neuronal survi val in cerebral cortex ischemic lesions. Astroglial reaction was appro ximately the same in the lesions in op/op mice, grafted and implanted op/op mice and C3H/HeJ mice, indicating that CSF-1 modulates microglia , but not the response of astrocytes to injury. The degree of neuronal survival was not correlated to the degree of microglial proliferation and intensity of their reaction. We report some indications that CSF- 1, in addition to modulation of microglia, may also act directly on ne urons.