Prenatal LPS increases inflammation in the substantia nigra of Gdnf heterozygous mice.
Prenatal systemic inflammation has been implicated in neurological diseases, but optimal animal models have not been developed. We investigated whether a partial genetic deletion of glial cell line-derived neurotrophic factor (Gdnf(+/-)) increased vulnerability of dopamine (DA) neurons to prenatal lipopolysaccharide (LPS). LPS [0.01 mg/kg intraperitoneal (i.p.)] or saline was administered to wild-type (WT) or Gdnf(+/-) pregnant mice on gestational day 9.5. Male offspring were examined at 3 weeks, 3 and 12 months of age. There was a progressive degeneration of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) with age in Gdnf(+/-) but not in WT mice, with no observed effects on locus coeruleus (LC) noradrenergic neurons or DA neurons of the ventral tegmental area. Inflammatory markers were elevated in SN of LPS treated offspring, with exacerbation in Gdnf(+/-) mice. Intracellular accumulation of α-synuclein (α-syn) immunoreactivity in DA neurons of SN was observed in all groups of Gdnf(+/-) and in WT mice with prenatal LPS, with altered distribution between pars reticulata (pr) and pars compacta (pc). The findings suggest that prenatal LPS leads to accelerated neuropathology in the SN with age, and that a partial loss of GDNF exacerbates these effects, providing a novel model for age-related neuropathology of the nigrostriatal DA system.
Granholm
Ann-Charlotte
AC
Department of Neurosciences, Medical University of South Carolina, Center on Aging, Charleston, SC 29425, USA. granholm@musc.edu
Zaman
Vandana
V
Godbee
Jennifer
J
Smith
Michael
M
Ramadan
Riad
R
Umphlet
Claudia
C
Randall
Patrick
P
Bhat
Narayan R
NR
Rohrer
Baerbel
B
Middaugh
Lawrence D
LD
Boger
Heather A
HA
D000367:Age Factors; D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006579:Heterozygote; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017072:Neostriatum / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000276:immunology*; D013378:Substantia Nigra / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
D051100:Glial Cell Line-Derived Neurotrophic Factor; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine