The GABA Developmental Shift Is Abolished by Maternal Immune Activation Already at Birth

Abstract

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.

Symptom improvement in children with autism spectrum disorder following bumetanide administration is associated with decreased GABA/glutamate ratios

“…It is thought that GABAergic signals are altered in ASD and that an elevated level of [Cl − ] i contributes to E-I imbalance during early brain development 46 . In mouse models of ASD, bumetanide was shown to function as a high-affinity specific inhibitor of NKCC1 that could [11][12][13][14] . However, direct neuropharmacological evidence for the action of bumetanide in humans is lacking, despite the promising therapeutic effects in ASD patients reported in several clinical studies.…”

“…The regulation of the intracellular neuronal chloride levels determines the efficacy of GABAergic inhibition and high levels can hinder the polarity from excitation to inhibition 10 . In animal models of autism, notably rats with intrauterine valproic acid injection 11,12 or maternal immune activation 13 , rats carrying the fragile X 11 or MECP2 mutation 14 , acute maternal administration of bumetanide, a NKCC1 chloride-importer inhibitor, before delivery switched the action of GABA from excitatory to inhibitory in the offspring, restoring both electrophysiological profile of the CA3 area of hippocampus, cerebellar purkinje cells or normal cerebral volumes.…”

Pregnancy data enable identification of relevant biomarkers and a partial prognosis of autism at birth

“…Experimental observations are in accord with this. Hippocampal and neocortical volumes are increased in an animal model of ASD and hippocampal neuron size grows during parturition and birth [25,29]. Neurons with immature features are present in the adolescent and adult human amygdala [57].…”

“…Neurons with immature properties have been observed in many pathological conditions in experimental models of ASD. High (Cl-)i and GABA excitatory actions are observed in immature neurons in MIA [25], maternal Valproate and Fragile X [30,61], and Rett syndrome [62] suggesting common global reaction to the pathogenic insult. Restoration of GABAergic inhibition also attenuates in humans and rodents the severity of ASD paving the way to novel therapeutic strategies based on selective actions on immature neurons [63,64].…”

“…Experimental data also suggest an in-utero pathogenesis of ASD [23][24][25][26][27][28]. Thus, maternal immune activation or valproate administration are associated with ASD [24,29] and early post-natal alterations are observed in genetic forms of autism [30].…”