CSF-1 controls cerebellar microglia and is required for motor function and social interaction

Abstract

Microglia, the brain resident macrophages, critically shape forebrain neuronal circuits. However, their precise function in the cerebellum is unknown. Here we show that human and mouse cerebellar microglia express a unique molecular program distinct from forebrain microglia. Cerebellar microglial identity was driven by the CSF-1R ligand CSF-1, independently of the alternate CSF-1R ligand, IL-34. Accordingly, CSF-1 depletion from Nestin+ cells led to severe depletion and transcriptional alterations of cerebellar microglia, while microglia in the forebrain remained intact. Strikingly, CSF-1 deficiency and alteration of cerebellar microglia were associated with reduced Purkinje cells, altered neuronal function, and defects in motor learning and social novelty interactions. These findings reveal a novel CSF-1–CSF-1R signaling-mediated mechanism that contributes to motor function and social behavior.

Microglial regional heterogeneity and its role in the brain

“…Two simultaneous earlier studies reported that IL-34, an alternate ligand of CSF1R which was expressed mainly by neurons in the brain, seemed to be vital in maintaining microglial numbers in a regional manner, as microglial density was reduced in IL-34deficient mice only in the cortex and striatum, but not in the cerebellum and brainstem [111,112]. A very recent study in CSF1-deficient mice also confirmed that CSF1 depletion affected the number of microglia in the cerebellum but not the frontal cerebral cortex [113]. It would be important to further understand whether this region-specific dependency on CSF1 and IL-34 is caused by difference in the neuronal expression of IL-34, or its microglial receptor CSF1R, or both, among brain areas.…”

“…Low Sirpa [136] Others (NF-κB, CD11b, MHCII, Tim3, etc.) Higher in human WM [66,75,76] Median [59,62,63,136] High [49] Median [59,62,63,136] Median [59,62,63,136] High [59,62,63,136] Cellular functions: Proliferation/replenish after ablation Both fast [42] Both fast [46,48] Both fast [44,45,104] Replenish fast [42] Fast [48] /replenish slower [42] Replenish fast [42] Protrusion toward ATP/ Phagocytosis/pruning Fast protrusion [52]/Low lysosome content in NAc [65] High surveillance [74,82] Slow protrusion [ [111,112] Hoxb8 − , [101]; Sensitive to CSF1 [113] but not IL-34 [111,112] Unknown system by crossing CX3CR1 creER mice with R26 Confetti reporter mice, Tay et al observed that microglia established a dense network with highly variable turnover rates in multiple brain regions, which challenges the concept of microglial longevity in a healthy brain [48]. They reported subtly (oneto-two cycles) more active cell division in hippocampal and cerebel...…”

Microglia: Same same, but different

“…Despite previous reports of cerebellar Purkinje cells expressing CSF-1R and their potential to be affected by the loss of CSF-1, the authors clearly excluded an expression of CSF-1R on calbindin-positive Purkinje cells that is in line with previous studies on the microglia-restricted expression of CSF-1R (Hagemeyer et al, 2017). Kana et al (2019) further demonstrated that the loss of cerebellar microglia led to a developmental defect of Purkinje cells most likely due to decreased microglia-mediated elimination of climbing fibers during early postnatal development. This results in an increase in spontaneous miniature excitatory postsynaptic currents in the remaining Purkinje cells.…”

“…In fact, the function of cerebellar microglia is poorly understood to date, as current literature focuses primarily on microglia in the forebrain, hippocampus, or cortex. Kana et al (2019) first performed bulk RNA sequencing of human forebrain and cerebellar microglia and identified that cerebellar microglia have distinct transcriptional profiles compared with forebrain microglia. Similar transcriptional differences of microglia in different brain regions were also found in mice.…”

Csf1 Deficiency Dysregulates Glial Responses to Demyelination and Disturbs CNS White Matter Remyelination

“…Both IL-34 and Csf1 are ligands for the same receptor, but they have distinct CNS distribution and cellular source [61,71]. IL-34 is produced by neurons and plays a vital role for microglial cells in the CNS grey matter, whereas astrocyte-derived Csf1 acts as the major ligand for the maintenance of white matter microglia [72]. Since Csf1R expression, the only receptor for Csf1, is prominent in microglia throughout the brain, Csf1R-/-mice have a more severe phenotype than the Csf1-/-, however, they exhibit increased neuronal density, elevated numbers of astrocytes but reduced numbers of oligodendrocytes and substantially poorer viability [67].…”