Immune activation during gestation leads to hippocampal neuronal alterations already at birth

Scientific papers  |  4 November 2018

Two of the most biologically complex and vulnerable periods are pregnancy and birth. Birth is a stressful event with a release of several stress molecules needed to facilitate the transition of the fetus to extrauterine life. Furthermore, throughout pregnancy the fetus is susceptible to different types of stressors including immune activation due to maternal infections (maternal immune activation (MIA)). Indeed, bacterial or viral infections during the first or second trimester in humans have been correlated with an increased risk of developing Autism. The in-utero Poly(I:C) mouse model of MIA has been extensively used to investigate the mechanisms leading to the neurological sequels. Using this model, in our recent publication in Cerebral Cortex1 we tested the hypothesis that an in-utero event such as MIA will lead to neuronal alterations already at birth. In our earlier studies2 we described an oxytocin-mediated neuroprotective abrupt GABA polarity shift during birth that is abolished in Autism. We report that in MIA pups at birth the hippocampal network activity is altered and hippocampal neurons have more exuberant apical arbors and dendrites than age-matched controls. Also, MIA abolished the oxytocin-mediated GABAergic inhibitory shift at birth and led to excitatory actions of GABA that persist until at least the 2nd postnatal week. Acute neuronal treatment with Bumetanide at birth restored GABAergic inhibitory action. These observations are reminiscent of those reported in rodent models of Autism and other neurodevelopmental disorders. Our findings both highlight the vulnerability of the critical periods of pregnancy and birth and stress the importance of the GABA developmental shift.

Morphophysiological alterations at birth in a mouse model of maternal immune activation (MIA). Confocal images of biocytin-filled hippocampal neurons from saline (A; control) and MIA (B; Poly(I:C)) offspring at birth and representative reconstructed apical arbors. C Average values of the intracellualr levels of chloirde (determined by the GABA driving force – DFGABA) in saline, MIA and after bumetanide acute treatment at birth . D Frequency of spontaneus glutamatergic postsynaptic currents in saline and MIA hippocampal neurons at birth. E Correlation of activity between pairs of active cells in saline and MIA hippocampal networks at birth. Representative image of a hippocampal slice at birth loaded with the fluorescent calcium sensor Fura-2AM, corresponding semiautomated cells contours detection and representative traces of flourescence emitted by cells. Modified from Fernandez et al., Cerebral Cortex, 2019
References :
1. Fernandez A, Dumon C, Guimond D, Tyzio R, Bonifazi P, Lozovaya N, Burnashev N, Ferrari DC, Ben-Ari Y. The GABA Developmental Shift Is Abolished by Maternal Immune Activation Already at Birth. Cerebral Cortex. 2019 Aug 14;29(9):3982-3992.
2. Tyzio R. et al. Oxytocin-mediated GABA inhibition during delivery attenuates Autism pathogenesis in Rodent Offspring. Science. 2014, 343 (6171): 675-679. Doi: 10.1126 / science.1247190