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

Amandine Fernandez,Nail Burnashev,Yehezkel Ben-Ari,Paolo Bonifazi,Diana C Ferrari,Damien Guimond,Camille Dumon,Roman Tyzio,Natalia Lozovaya

doi:10.1093/cercor/bhy279

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.

Highlights

We report that maternal immune activation (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
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
We report that Poly(I:C)-induced MIA alters the transient excitatory to inhibitory switch of GABA at birth due to higher [Cl−]i levels as attested by measures of the GABAAR driving force and its restoration by bumetanide

Summary

Introduction

Epidemiological studies indicate that maternal infection and inflammatory processes during pregnancy are risk factors for developmental disorders in offspring (Patterson 2002, 2009; Atladóttir et al 2010, 2012; Brown 2012; Knuesel et al 2014; Lyall et al 2014; Estes and Mcallister 2016; Zerbo et al 2015). Poly(I:C)induced MIA offspring was shown to exhibit pleiotropic pathophysiological disturbances This included a loss of neuronal layer identity with somatosensory cortical disorganized patches (Kim et al 2017; Shin Yim et al 2017); a reduction of parvalbumin interneurons’ perineural nets (Paylor et al 2016) and an altered GABAergic (γ-aminobutyric acid (GABA)) transcriptome (Richetto et al 2014) leading to decreased GAD67 (glutamate decarboxylase) expression in the prefrontal cortex; and in the hippocampus, synaptic deficits (Giovanoli, Weber-Stadlbauer, et al 2016) and alterations of place cell firing (Wolff and Bilkey 2015). Neurons with immature features might constitute a leading pathogenic mechanism perturbing relevant brain network oscillations In keeping with this hypothesis, Corradini and colleagues have recently shown that the developmental GABA excitatory to inhibitory shift is not present in cortical neurons of MIA offspring, leading to paradoxical excitatory actions of GABA in P20 rodents (Corradini et al 2018). Whether these alterations are present earlier and in particular at birth is not known

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Conclusion