Epidemiological and experimental studies suggest that maternal immune activation (MIA) leads to developmental brain disorders, but whether the pathogenic mechanism impacts neurons already at birth is not known. We now report that MIA abolishes in mice the oxytocin-mediated delivery γ-aminobutyric acid (GABA) shift from depolarizing to hyperpolarizing in CA3 pyramidal neurons, and this is restored by the NKCC1 chloride importer antagonist bumetanide. Furthermore, MIA hippocampal pyramidal neurons at birth have a more exuberant apical arbor organization and increased apical dendritic length than age-matched controls. The frequency of spontaneous glutamatergic postsynaptic currents is also increased in MIA offspring, as well as the pairwise correlation of the synchronized firing of active cells in CA3. These alterations produced by MIA persist, since at P14–15 GABA action remains depolarizing, produces excitatory action, and network activity remains elevated with a higher frequency of spontaneous glutamatergic postsynaptic currents. Therefore, the pathogenic actions of MIA lead to important morphophysiological and network alterations in the hippocampus already at birth.

Background Genes and gluten are necessary, but insufficient to cause celiac disease (CeD), as risk alleles (DQ2 or DQ8) are prevalent in ~30–40% of the healthy population consuming gluten. Gut microbiota shifts and infections have been proposed as risk modulators. Biogeographic characterization of the microbiota in CeD patients and its functional significance are limited, particularly at the duodenum, the main site of inflammation. Aims We studied microbiota composition and predicted function along the gastrointestinal tract and investigated the impact of host genetics and CeD activity. Methods We used 16S rRNA gene sequencing (Illumina) and predicted gene function analysis (PICRUSt2), to study the microbiota in duodenal biopsies (D1, D2 and D3), duodenal aspirates, and fecal samples from patients with active CeD (n= 24) (biopsy and serology confirmed) and controls (non-celiac, n= 41). CeD alleles were determined in consented participants using DQ-CD typing. Small intestinal samples from controls (DQ2-/- = 14; DQ2+/- = 7) and CeD (DQ2+/- = 12) were used for further analysis and to colonize C57BL/6 germ-free mice for gluten metabolism studies. Results Microbiota community composition and predicted function was mainly determined by intestinal location (P= 0.001). Within the duodenum, but not in stool, CeD patients had increased abundance of opportunistic pathogens. Escherichia coli was increased in D1, Streptococcus pneumoniae in D2, and Neisseria in D3 versus controls. Predicted bacterial protease and peptidase genes were altered in CeD DQ2+/- patients versus DQ2-/- controls. In DQ2+/- controls, fewer predicted bacterial genes were altered compared to CeD DQ2+/- patients. Impaired capacity to metabolize gluten was confirmed in germ-free mice colonized with microbiota from CeD (DQ2+/-), but not DQ2+/- or DQ2-/- controls. Conclusions In the duodenum, CeD is associated with increased opportunistic pathogens and altered bacterial proteolytic profile. These are not determined by genetic predisposition, as CeD and controls with similar genetic background differed in its predicted bacterial proteolytic function, which was confirmed in mice colonized with duodenal microbiota using these cohorts. Our study highlights the need for defining sampling location in studies investigating the role of microbiota in CeD. Funding Agencies CAG, CCC, CIHR