Inhibition of colony-stimulating factor 1 receptor early in disease ameliorates motor deficits in SCA1 mice

Abstract

BackgroundPolyglutamine (polyQ) expansion in the protein Ataxin-1 (ATXN1) causes spinocerebellar ataxia type 1 (SCA1), a fatal dominantly inherited neurodegenerative disease characterized by motor deficits, cerebellar neurodegeneration, and gliosis. Currently, there are no treatments available to delay or ameliorate SCA1. We have examined the effect of depleting microglia during the early stage of disease by using PLX, an inhibitor of colony-stimulating factor 1 receptor (CSFR1), on disease severity in a mouse model of SCA1.MethodsTransgenic mouse model of SCA1, ATXN1[82Q] mice, and wild-type littermate controls were treated with PLX from 3 weeks of age. The effects of PLX on microglial density, astrogliosis, motor behavior, atrophy, and gene expression of Purkinje neurons were examined at 3 months of age.ResultsPLX treatment resulted in the elimination of 70–80% of microglia from the cerebellum of both wild-type and ATXN1[82Q] mice. Importantly, PLX ameliorated motor deficits in SCA1 mice. While we have not observed significant improvement in the atrophy or disease-associated gene expression changes in Purkinje neurons upon PLX treatment, we have detected reduced expression of pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) and increase in the protein levels of wild-type ataxin-1 and post-synaptic density protein 95 (PSD95) that may help improve PN function.ConclusionsA decrease in the number of microglia during an early stage of disease resulted in the amelioration of motor deficits in SCA1 mice.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0880-z) contains supplementary material, which is available to authorized users.

Astroglia contribute to the pathogenesis of spinocerebellar ataxia Type 1 (SCA1) in a biphasic, stage‐of‐disease specific manner

“…We injected ATXN1[82Q];IKKβ F/F ;Slc1a3‐cre/ER T mice with TMX at 8 weeks of age for the early disease stage time point, and at 16 weeks, for the late stage time point. At 8 weeks of age, the mutant ataxin‐1 is actively being expressed in Purkinje neurons (postnatal day 10), the astrogliosis already initiated (at 3 weeks), but there is no detectable change in the motor behavior of ATXN1[82Q] mice (i.e., the mice were at the pre‐symptomatic stage; Ebner et al, ; Cvetanovic et al, ; Qu et al, ). At 16 weeks, ATXN1[82Q] exhibit motor deficits and atrophy of Purkinje neuron dendrites (Duvick et al, ).…”

Microglial regulation of satiety and cognition

“…Regardless of whether these compounds ablate microglia or suppress a subset of microglial‐related genes, these cells can no longer be seen in the brain after 3 weeks of treatment with this compound and microglia‐typical functions, such as the response to LPS, are impaired . Microglial‐related pathologies can also be improved with these compounds . However, appetite and feeding remain largely unaffected, at least in adults.…”

“…15 Microglial-related pathologies can also be improved with these compounds. 75,106 However, appetite and feeding remain largely unaffected, at least in adults. As such, the few studies that have investigated food intake or body weight after exposure to PLX compounds report them to be unchanged in chow-fed young adult mice.…”

“…Learning-induced microglial activation may also orchestrate strategic remodelling of dendritic spines, which is essential for successful cognition. Figure (95) LPS in arcute nucleus slice preparations: mouse & rat (108) ICV TLR2 activation: mouse (97) ICV minocycline: rat (108) Cx3cr1-Dtr rats (acute conditional microglial knockout: rat (20) PLX5622 in HFD: mouse (106) Drinking water depletion minocycline: mouse (65) CSFR1 inhibition with PLX compounds: mouse (21,106,107) Ara-C (in cases of normal chow): mouse (102) Ara-C (in cases of HFD): mouse (102) Annexin-V (in cases of HFD): mouse (65) Annexin-V (in cases of normal chow): mouse (65) Minocycline: humans (112) Microglial leptin receptor depletion: mouse (110) Embroyonic microglial depletion: mouse (111) ICV visfatin: mouse (96) Obesity (males but not females): mouse & rat (98,101,104) HFD: mouse & rat (99,100,101) the basolateral amygdala, a circuit that interacts with the orexigenic networks of the PVT to establish valence in satiety-sensing. 115,116 In support of this idea, we see greater neuronal activation in the PVT in response to feeding in the absence of microglia.…”

Microglia responses to interleukin‐6 and type I interferons in neuroinflammatory disease

“…Therapeutic targeting of microglia has been demonstrated to be effective in some circumstances. Administration of CSF1R inhibitors ablates microglia from the CNS and is beneficial in limiting damage and promoting recovery in a wide variety of animal models with severe neurodegeneration or tissue damage (Acharya et al, 2016;Asai et al, 2015;Dagher et al, 2015;Feng et al, 2016Feng et al, , 2017Janova et al, 2018;Klein et al, 2015;Lee, Shi, Fan, West, & Zhang, 2018;Li et al, 2017;Nissen, Thompson, West, & Tsirka, 2018;Qu et al, 2017;Rice et al, 2015;Sosna et al, 2018;Spangenberg et al, 2016;Walter & Crews, 2017). However, microglia ablation has not always been shown to be beneficial and is severely damaging in other neurodegenerative mouse models Spiller et al, 2018;Szalay et al, 2016;Wheeler, Sariol, Meyerholz, & Perlman, 2018;Yang et al, 2018).…”