Early Life Stress Disrupts Hippocampal Development via Lipopolysaccharide-Binding Protein
Wei L, Simen A, Mane S, Kaffman A. Early life stress inhibits expression of a novel innate immune pathway in the developing hippocampus. Neuropsychopharmacology 2012;37(2):567-580. doi: 10.1038/npp.2011.239.
Background: Early life stress has been shown to cause enduring changes in emotional and cognitive behavior. The authors examined how brief daily separation (BDS) of mouse pups from their dams affects hippocampal development. Using a genome-wide screen, they identified lipopolysaccharide-binding protein (LBP), traditionally known for immune function, as a gene markedly affected by BDS during a critical developmental period.
Hypothesis: This study hypothesized that early life stress inhibits hippocampal LBP expression during development, thereby disrupting synaptic maturation and leading to anxiety-like and cognitive deficits in adulthood.
Methods: The authors subjected BALB/cByj mouse pups to BDS from postnatal day (PND) 1–21 and conducted behavioral, molecular and anatomical analyses. They also tested LBP knockout (k.o.) mice. Dendritic morphology in hippocampal CA1 neurons was quantified using Golgi staining analyzed with Neurolucida, and LBP expression was examined by quantitative PCR, in situ hybridization and immunohistochemistry.
Results: BDS impaired adult performance in hippocampal-dependent learning and increased anxiety-like behavior. BDS and acute maternal separation reduced LBP mRNA and protein in the hippocampus but not plasma. LBP colocalized with PSD95 and contacted microglia processes. LBP k.o. mice displayed increased dendritic spine density without changes in dendritic length, abnormal spine morphology, impaired object recognition and elevated anxiety-like behaviors resembling BDS effects.
Conclusions: The study demonstrates that LBP is required for normal hippocampal synaptic development. Early life stress reduces hippocampal LBP expression, potentially impairing microglia-mediated synaptic pruning and leading to persistent behavioral abnormalities in adulthood.
