Maternal Immune Activation Delays Excitatory-to-Inhibitory Gamma-Aminobutyric Acid Switch in Offspring.
Biol Psychiatry
; 83(8): 680-691, 2018 04 15.
Article
en En
| MEDLINE
| ID: mdl-29146047
ABSTRACT
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 polyinosinicpolycytidylic acid. Neuronal development was assessed by means of electrophysiological, optical, and biochemical analyses.RESULTS:
Prenatal exposure to polyinosinicpolycytidylic 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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Complicaciones del Embarazo
/
Efectos Tardíos de la Exposición Prenatal
/
Corteza Cerebral
/
Potenciales Postsinápticos Excitadores
/
Epilepsia
/
Potenciales Postsinápticos Inhibidores
/
Ácido gamma-Aminobutírico
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Pregnancy
Idioma:
En
Revista:
Biol Psychiatry
Año:
2018
Tipo del documento:
Article
País de afiliación:
Italia