Prenatal LPS increases Inflammation in the Substantia Nigra of Gdnf Heterozygous Mice

Department of Neurosciences, Medical University of South Carolina, Center on Aging, Charleston, SC 29425, USA.
Brain Pathology (Impact Factor: 3.84). 10/2010; 21(3):330-48. DOI: 10.1111/j.1750-3639.2010.00457.x
Source: PubMed


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.

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    • "If we consider that prenatal infection is a general vulnerability factor conferring increased susceptibility to a range of different neurodevelopmental disorders, then it is more important than ever to create multifactorial models, combining either multiple environmental risk factors or an environmental risk factor on a background of genetic risk. This approach has been used by groups examining the interactive effects of prenatal immune activation together with exposure to environmental neurotoxins (Ling et al., 2004a,b, 2006) or effects of prenatal immune activation in interaction with genes implicated in the etiology of disorders such as schizophrenia and Parkinson's disease (Granholm et al., 2010; Ibi et al., 2010; Ehninger et al., 2012; Vuillermot et al., 2012). In theory, such investigations may allow us to identify which combinations of etiological factors are more likely to result in one particular disorder (e.g., schizophrenia) versus another (e.g., autism). "
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