Genetically induced brain inflammation by <i>Cnp</i> deletion transiently benefits from microglia depletion

Abstract

Reduced expression of 2'-3'-cyclic nucleotide 3'-phosphodiesterase (<i>Cnp</i>) in humans and mice causes white matter inflammation and catatonic signs. These consequences are experimentally alleviated by microglia ablation <i>via</i> colony-stimulating factor 1 receptor (CSF1R) inhibition using PLX5622. Here we address for the first time preclinical topics crucial for translation, most importantly <i>1</i>) the comparison of 2 long-term PLX5622 applications (prevention and treatment) <i>vs.</i> 1 treatment alone, <i>2</i>) the correlation of catatonic signs and executive dysfunction, <i>3</i>) the phenotype of leftover microglia evading depletion, and <i>4</i>) the role of intercellular interactions for efficient CSF1R inhibition. Based on our <i>Cnp^-/-</i> mouse model and <i>in vitro</i> time-lapse imaging, we report the unexpected discovery that microglia surviving under PLX5622 display a highly inflammatory phenotype including aggressive premortal phagocytosis of oligodendrocyte precursor cells. Interestingly, ablating microglia <i>in vitro</i> requires mixed glial cultures, whereas cultured pure microglia withstand PLX5622 application. Importantly, 2 extended rounds of CSF1R inhibition are not superior to 1 treatment regarding any readout investigated (magnetic resonance imaging and magnetic resonance spectroscopy, behavior, immunohistochemistry). Catatonia-related executive dysfunction and brain atrophy of <i>Cnp^-/-</i> mice fail to improve under PLX5622. To conclude, even though microglia depletion is temporarily beneficial and worth pursuing, complementary treatment strategies are needed for full and lasting recovery.-Fernandez Garcia-Agudo, L., Janova, H., Sendler, L. E., Arinrad, S., Steixner, A. A., Hassouna, I., Balmuth, E., Ronnenberg, A., Schopf, N., van der Flier, F. J., Begemann, M., Martens, H., Weber, M. S., Boretius, S., Nave, K.-A., Ehrenreich, H. Genetically induced brain inflammation by <i>Cnp</i> deletion transiently benefits from microglia depletion.