TY - JOUR
T1 - Neurofibromatosis 1 - Mutant microglia exhibit sexually-dimorphic cyclic AMP-dependent purinergic defects
AU - Elmadany, Nirmeen
AU - Logiacco, Francesca
AU - Buonfiglioli, Alice
AU - Haage, Verena C.
AU - Wright-Jin, Elizabeth C.
AU - Schattenberg, Alexander
AU - Papawassiliou, Roxane M.
AU - Kettenmann, Helmut
AU - Semtner, Marcus
AU - Gutmann, David H.
N1 - Funding Information:
We thank Regina Piske and Nadine Scharek, for their excellent technical assistance. The work was supported by the NeuroCure Cluster of Excellence grant to H.K., a National Cancer Institute grant (1- R01-CA214146-01 to D.H.G.) and a Berlin Institute of Health/ Einstein fellowship grant to D.H.G. and H.K. D.H.G. is an Alexander von Humboldt Fellow. N.E. is a DAAD scholar. This work was also supported by services provided by the Advanced Light Microscopy facility (MDC, Berlin).
Funding Information:
We thank Regina Piske and Nadine Scharek, for their excellent technical assistance. The work was supported by the NeuroCure Cluster of Excellence grant to H.K. a National Cancer Institute grant (1-R01-CA214146-01 to D.H.G.) and a Berlin Institute of Health/ Einstein fellowship grant to D.H.G. and H.K. D.H.G. is an Alexander von Humboldt Fellow. N.E. is a DAAD scholar. This work was also supported by services provided by the Advanced Light Microscopy facility (MDC, Berlin). N.E. A.S. and M.S. performed the electrophysiology experiments; N.E. F.L. and R.P. performed the phagocytosis experiment; V.H. performed the qRT-PCR experiments; F.L. performed the laser lesion experiments; A.B. performed density and multiplex ELISA experiments. E.L.W.-J. performed additional experiments during the execution of this project, N.E. E.C.W.-J. and M.S. wrote the first draft of the manuscript and prepared the figures; N.E. and M.S. supervised the trainees (R.P. and A.S.) who participated in performing the experiments; M.S. H.K. and D.H.G. designed the experiments; H.K. and D.H.G. oversaw the studies, mentored the trainees, revised the manuscript and provided funding for this project. No protein or modeling script datasets were produced in this study. The authors declare no relevant conflicts of interest.
Publisher Copyright:
© 2020 The Authors
PY - 2020/10
Y1 - 2020/10
N2 - As critical regulators of brain homeostasis, microglia are influenced by numerous factors, including sex and genetic mutations. To study the impact of these factors on microglia biology, we employed genetically engineered mice that model Neurofibromatosis type 1 (NF1), a disorder characterized by clinically relevant sexually dimorphic differences. While microglia phagocytic activity was reduced in both male and female heterozygous Nf1 mutant (Nf1+/−) mice, purinergic control of phagocytosis was only affected in male Nf1+/− mice. ATP-induced P2Y-mediated membrane currents and P2RY12-dependent laser lesion-induced accumulation of microglial processes were also only impaired in male, but not female Nf1+/−, microglia. These defects resulted from Nf1+/− male-specific defects in cyclic AMP regulation, rather than from changes in purinergic receptor expression. Cyclic AMP elevation by phosphodiesterase blockade restored the male Nf1+/− microglia defects in P2Y-dependent membrane currents and process motility. Taken together, these data establish a sex-by-genotype interaction important to microglia function in the adult mouse brain.
AB - As critical regulators of brain homeostasis, microglia are influenced by numerous factors, including sex and genetic mutations. To study the impact of these factors on microglia biology, we employed genetically engineered mice that model Neurofibromatosis type 1 (NF1), a disorder characterized by clinically relevant sexually dimorphic differences. While microglia phagocytic activity was reduced in both male and female heterozygous Nf1 mutant (Nf1+/−) mice, purinergic control of phagocytosis was only affected in male Nf1+/− mice. ATP-induced P2Y-mediated membrane currents and P2RY12-dependent laser lesion-induced accumulation of microglial processes were also only impaired in male, but not female Nf1+/−, microglia. These defects resulted from Nf1+/− male-specific defects in cyclic AMP regulation, rather than from changes in purinergic receptor expression. Cyclic AMP elevation by phosphodiesterase blockade restored the male Nf1+/− microglia defects in P2Y-dependent membrane currents and process motility. Taken together, these data establish a sex-by-genotype interaction important to microglia function in the adult mouse brain.
KW - Brain
KW - Microglia
KW - Neurofibromin
KW - P2RY12
KW - Purinergic signaling
KW - Sex differences
KW - cAMP
UR - http://www.scopus.com/inward/record.url?scp=85089817025&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2020.105030
DO - 10.1016/j.nbd.2020.105030
M3 - Article
C2 - 32736084
AN - SCOPUS:85089817025
SN - 0969-9961
VL - 144
JO - Neurobiology of Disease
JF - Neurobiology of Disease
M1 - 105030
ER -