Cross-Sectional Dating of Novel Haplotypes of HERV-K 113 and HERV-K 115 Indicate These Proviruses Originated in Africa before Homo sapiens

The human genome, human endogenous retroviruses (HERV), of which HERV-K113 and HERV-K115 are the only known full-length proviruses that are insertionally polymorphic. Although a handful of previously published papers have documented their prevalence in the global population; to date, there has been no report on their prevalence in the United States population. Here, we studied the geographic distribution of K113 and K115 among 156 HIV-1+ subjects from the United States, including African Americans, Hispanics, and Caucasians. In the individuals studied, we found higher insertion frequencies of K113 (21%) and K115 (35%) in African Americans compared with Caucasians (K113 9% and K115 6%) within the United States. We also report the presence of three single nucleotide polymorphism sites in the K113 5′ long terminal repeats (LTRs) and four in the K115 5′ LTR that together constituted four haplotypes for K113 and five haplotypes for K115. HERV insertion times can be estimated from the sequence differences between the 5′ and 3′ LTR of each insertion, but this dating method cannot be used with HERV-K115. We developed a method to estimate insertion times by applying coalescent inference to 5′ LTR sequences within our study population and validated this approach using an independent estimate derived from the genetic distance between K113 5′ and 3′ LTR sequences. Using our method, we estimated the insertion dates of K113 and K115 to be a minimum of 800,000 and 1.1 million years ago, respectively. Both these insertion dates predate the emergence of anatomically modern Homo sapiens

Prenatal Activation of Microglia Induces Delayed Impairment of Glutamatergic Synaptic Function

BACKGROUND: Epidemiological studies have linked maternal infection during pregnancy to later development of neuropsychiatric disorders in the offspring. In mice, experimental inflammation during embryonic development impairs behavioral and cognitive performances in adulthood. Synaptic dysfunctions may be at the origin of cognitive impairments, however the link between prenatal inflammation and synaptic defects remains to be established. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we show that prenatal alteration of microglial function, including inflammation, induces delayed synaptic dysfunction in the adult. DAP12 is a microglial signaling protein expressed around birth, mutations of which in the human induces the Nasu-Hakola disease, characterized by early dementia. We presently report that synaptic excitatory currents in mice bearing a loss-of-function mutation in the DAP12 gene (DAP12(KI) mice) display enhanced relative contribution of AMPA. Furthermore, neurons from DAP12(KI) P0 pups cultured without microglia develop similar synaptic alterations, suggesting that a prenatal dysfunction of microglia may impact synaptic function in the adult. As we observed that DAP12(KI) microglia overexpress genes for IL1beta, IL6 and NOS2, which are inflammatory proteins, we analyzed the impact of a pharmacologically-induced prenatal inflammation on synaptic function. Maternal injection of lipopolysaccharides induced activation of microglia at birth and alteration of glutamatergic synapses in the adult offspring. Finally, neurons cultured from neonates born to inflamed mothers and cultured without microglia also displayed altered neuronal activity. CONCLUSION/SIGNIFICANCE: Our results demonstrate that prenatal inflammation is sufficient to induce synaptic alterations with delay. We propose that these alterations triggered by prenatal activation of microglia provide a cellular basis for the neuropsychiatric defects induced by prenatal inflammation