title: Colony-stimulating factor 1 receptor blockade prevents fractionated whole-brain irradiation-induced memory deficits.
abstract: Primary central nervous system (CNS) neoplasms and brain metastases are routinely treated with whole-brain radiation. Long-term survival occurs in many patients, but their quality of life is severely affected by the development of cognitive deficits, and there is no treatment to prevent these adverse effects. Neuroinflammation, associated with activation of brain-resident microglia and infiltrating monocytes, plays a pivotal role in loss of neurological function and has been shown to be associated with acute and long-term effects of brain irradiation. Colony-stimulating factor 1 receptor (CSF-1R) signaling is essential for the survival and differentiation of microglia and monocytes. Here, we tested the effects of CSF-1R blockade by PLX5622 on cognitive function in mice treated with three fractions of 3.3 Gy whole-brain irradiation.
  
  
  
  Young adult C57BL/6J mice were given three fractions of 3.3 Gy whole-brain irradiation while they were on diet supplemented with PLX5622, and the effects on periphery monocyte accumulation, microglia numbers, and neuronal functions were assessed.
  
  
  
  The mice developed hippocampal-dependent cognitive deficits at 1 and 3 months after they received fractionated whole-brain irradiation. The impaired cognitive function correlated with increased number of periphery monocyte accumulation in the CNS and decreased dendritic spine density in hippocampal granule neurons. PLX5622 treatment caused temporary reduction of microglia numbers, inhibited monocyte accumulation in the brain, and prevented radiation-induced cognitive deficits.
  
  
  
  Blockade of CSF-1R by PLX5622 prevents fractionated whole-brain irradiation-induced memory deficits. Therapeutic targeting of CSF-1R may provide a new avenue for protection from radiation-induced memory deficits.
authors: Brain and Spinal Injury Center, University of California, 1001 Potrero Ave, Bldg. 1, Room 101, San Francisco, CA, 94110, USA.|Department of Physical Therapy and Rehabilitation Science, University of California, San Francisco, CA, USA.
authors: Xi
authors: X
authors: Feng
authors: Brain and Spinal Injury Center, University of California, 1001 Potrero Ave, Bldg. 1, Room 101, San Francisco, CA, 94110, USA.|Department of Physical Therapy and Rehabilitation Science, University of California, San Francisco, CA, USA.
authors: Timothy D
authors: TD
authors: Jopson
authors: Brain and Spinal Injury Center, University of California, 1001 Potrero Ave, Bldg. 1, Room 101, San Francisco, CA, 94110, USA.|Department of Physical Therapy and Rehabilitation Science, University of California, San Francisco, CA, USA.
authors: Maria Serena
authors: MS
authors: Paladini
authors: Department of Neurological Surgery, University of California, San Francisco, CA, USA.
authors: Sharon
authors: S
authors: Liu
authors: Plexxikon Inc, Berkeley, CA, USA.
authors: Brian L
authors: BL
authors: West
authors: Department of Neurological Surgery, University of California, San Francisco, CA, USA.|Department of Pediatrics, University of California, San Francisco, CA, USA.
authors: Nalin
authors: N
authors: Gupta
authors: Brain and Spinal Injury Center, University of California, 1001 Potrero Ave, Bldg. 1, Room 101, San Francisco, CA, 94110, USA. susanna.rosi@ucsf.edu.|Department of Physical Therapy and Rehabilitation Science, University of California, San Francisco, CA, USA. susanna.rosi@ucsf.edu.|Department of Neurological Surgery, University of California, San Francisco, CA, USA. susanna.rosi@ucsf.edu.
authors: Susanna
authors: S
authors: Rosi
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000528:radiation effects*; D008297:Male; D008569:Memory Disorders / Q000378:metabolism* / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D011830:Radiation Effects; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D000631:Aminopyridines; D011758:Pyrroles; C000600259:pexidartinib; D016186:Receptor, Macrophage Colony-Stimulating Factor
keywords: CSF-1R; Cognition; Whole-brain irradiation