Background: The association between maternal infection and neurodevelopmental defects in progeny is well established, although the biological mechanisms and the pathogenic trajectories involved have not been defined. Methods: Pregnant dams were injected intraperitoneally at gestational day 9 with polyinosinic:polycytidylic acid. Neuronal development was assessed by means of electrophysiological, optical, and biochemical analyses. Results: Prenatal exposure to polyinosinic:polycytidylic acid causes an imbalanced expression of the Na+-K+-2Cl- cotransporter 1 and the K+-Cl- cotransporter 2 (KCC2). This results in delayed gamma-aminobutyric acid switch and higher susceptibility to seizures, which endures up to adulthood. Chromatin immunoprecipitation experiments reveal increased binding of the repressor factor RE1-silencing transcription (also known as neuron-restrictive silencer factor) to position 509 of the KCC2 promoter that leads to downregulation of KCC2 transcription in prenatally exposed offspring. Interleukin-1 receptor type I knockout mice, which display braked immune response and no brain cytokine elevation upon maternal immune activation, do not display KCC2/Na+-K+-2Cl- cotransporter 1 imbalance when implanted in a wild-type dam and prenatally exposed. Notably, pretreatment of pregnant dams with magnesium sulfate is sufficient to prevent the early inflammatory state and the delay in excitatory-to-inhibitory switch associated to maternal immune activation. Conclusions: We provide evidence that maternal immune activation hits a key neurodevelopmental process, the excitatory-to-inhibitory gamma-aminobutyric acid switch; defects in this switch have been unequivocally linked to diseases such as autism spectrum disorder or epilepsy. These data open the avenue for a safe pharmacological treatment that may prevent the neurodevelopmental defects caused by prenatal immune activation in a specific pregnancy time window.
Maternal immune activation delays excitatory-to-inhibitory gamma-aminobutyric acid switch in offspring / I. Corradini, E. Focchi, M. Rasile, R. Morini, G. Desiato, R. Tomasoni, M. Lizier, E. Ghirardini, R. Fesce, D. Morone, I. Barajon, F. Antonucci, D. Pozzi, M. Matteoli. - In: BIOLOGICAL PSYCHIATRY. - ISSN 0006-3223. - 83:8(2018 Apr), pp. 680-691.
|Titolo:||Maternal immune activation delays excitatory-to-inhibitory gamma-aminobutyric acid switch in offspring|
|Parole Chiave:||epilepsy; GABA switch; KCC2; maternal immune activation; biological psychiatry|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||apr-2018|
|Data ahead of print / Data di stampa:||14-nov-2017|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.biopsych.2017.09.030|
|Appare nelle tipologie:||01 - Articolo su periodico|