Dissociation of genotype-dependent cognitive and motor behavior in a strain of aging mice devoid of the prion protein.

The prion glycoprotein (PrPC) is highly expressed in the nervous system as well as in other organs. Its functional roles in behavior have been examined mainly in non co-isogenic, wild-type and PrPC-deficient mice, which showed both age- and genotype-dependent differences. In general, however, effects of genetic background upon behavioral tests are mostly unclear when applied to aging rodents. The present study aimed to determine the effect of deletion of the prion protein on behavior of isogenic mice across different ages. We disclosed a genotype-dependent behavioral dissociation between either motor or cognitive tests, as a function of both age and test type. Remarkably, we also detected a clear age- and genotype-dependent difference in the variability of performance in a cognitive test. The current findings are relevant for both the interpretation of PrPC-related behavior, as well as for issues of reproducibility in studies of rodent behavior.

Neonatal infection leads to increased susceptibility to Aß oligomer-induced brain inflammation, synapse loss and cognitive impairment in mice.

Harmful environmental stimuli during critical stages of development can profoundly affect behavior and susceptibility to diseases. Alzheimer disease (AD) is the most frequent neurodegenerative disease, and evidence suggest that inflammatory conditions act cumulatively, contributing to disease onset. Here we investigated whether infection early in life can contribute to synapse damage and cognitive impairment induced by amyloid-ß oligomers (AßOs), neurotoxins found in AD brains. To this end, wild-type mice were subjected to neonatal (post-natal day 4) infection by Escherichia coli (1 × 104 CFU/g), the main cause of infection in low-birth-weight premature infants in the US. E. coli infection caused a transient inflammatory response in the mouse brain starting shortly after infection. Although infected mice performed normally in behavioral tasks in adulthood, they showed increased susceptibility to synapse damage and memory impairment induced by low doses of AßOs (1 pmol; intracerebroventricular) in the novel object recognition paradigm. Using in vitro and in vivo approaches, we show that microglial cells from E. coli-infected mice undergo exacerbated activation when exposed to low doses of AßOs. In addition, treatment of infected pups with minocycline, an antibiotic that inhibits microglial pro-inflammatory polarization, normalized microglial response to AßOs and restored normal susceptibility of mice to oligomer-induced cognitive impairment. Interestingly, mice infected with by E. coli (1 × 104 CFU/g) during adolescence (post-natal day 21) or adulthood (post-natal day 60) showed normal cognitive performance even in the presence of AßOs (1 pmol), suggesting that only infections at critical stages of development may lead to increased susceptibility to amyloid-ß-induced toxicity. Altogether, our findings suggest that neonatal infections can modulate microglial response to AßOs into adulthood, thus contributing to amyloid-ß-induced synapse damage and cognitive impairment.