Reduced inhibition underlies early life LPS exposure induced-cognitive impairment: Prevention by environmental enrichment

Abstract

Early life immune activation has negative effects on the development of central nervous system and cognitive function, yet the underlying mechanism remains unclear. Increasing evidence has demonstrated that inflammation induces changes in microglia morphology, which lead to excessive synaptic pruning and improper function of neural circuits. Therefore, we hypothesized that early immune activation induced microglia activation, contributing to synaptic and cognitive impairments in adolescent mice. To establish the animal model of early immune activation, pups received a single intraperitoneal injection of 100 μg/kg lipopolysaccharide (LPS) on postnatal 10 (P10). Environmental enrichment (EE) was conducted four hours per day during P10-P38. Behavioral tests were performed by open field (P39), elevated plus-maze (P40) and Y maze tests (P41). The protein levels of glutamic acid decarboxylas67 (GAD67), parvalbumin (PV), vesicular gaba amino acid transporter (vGAT) and vesicular glutamate transporters (vGLUT1) were determined in the hippocampi and medial prefrontal cortex (mPFC). The protein levels of nuclear factor κB (NF-κB)/p65, NF-κB/p50, interleukin-1β (IL-1β), tumor necrosis factor - ɑ (TNF-ɑ) were determined in the hippocampi. The dendritic spine density was evaluated in the CA1 of the hippocampus. In our study, we showed that early life LPS exposure induced microglia activation and excessive inhibitory synapse engulfment, decreased number of perisomatic puncta on both inhibitory PV interneurons and excitatory neurons, which might contribute to excitation/inhibition imbalance, dendritic spine loss, and cognitive impairment in adolescent mice. Notably, EE rescued most of these abnormalities and improved cognitive impairment. In conclusion, our study demonstrated that reduced inhibition might contribute to early life LPS exposure induced-cognitive impairment. We also provided the possibility of the protective role of EE in rescuing these long-term adverse effects.

Keywords: Cognitive impairment; Environmental enrichment; Immune activation; Inhibitory input.