Distinct Defects in Synaptic Differentiation of Neocortical Neurons in Response to Prenatal Valproate Exposure.

Yoko Iijima,Josef Bischofberger,Takatoshi Iijima,Peter Scheiffele,Katharina Behr,Barbara Biemans

doi:10.1038/srep27400

Yoko Iijima, Josef Bischofberger + Show 4 more

Open Access

https://doi.org/10.1038/srep27400

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Abstract

Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders characterized by impairments in social interactions and stereotyped behaviors. Valproic acid (VPA) is frequently used to treat epilepsy and bipolar disorders. When taken during pregnancy, VPA increases the risk of the unborn child to develop an ASD. In rodents, in utero VPA exposure can precipitate behavioral phenotypes related to ASD in the offspring. Therefore, such rodent models may allow for identification of synaptic pathophysiology underlying ASD risk. Here, we systematically probed alterations in synaptic proteins that might contribute to autism-related behavior in the offspring of in utero VPA-exposed mice. Moreover, we tested whether direct VPA exposure of cultured neocortical neurons may recapitulate the molecular alterations seen in vivo. VPA-exposed neurons in culture exhibit a significant increase in the number of glutamatergic synapses accompanied by a significant decrease in the number of GABAergic synapses. This shift in excitatory/inhibitory balance results in substantially increased spontaneous activity in neuronal networks arising from VPA-exposed neurons. Pharmacological experiments demonstrate that the alterations in GABAergic and glutamatergic synaptic proteins and structures are largely caused by inhibition of histone deacetylases. Therefore, our study highlights an epigenetic mechanism underlying the synaptic pathophysiology in this ASD model.

Highlights

The impact of in utero Valproic acid (VPA) exposure has been explored in rodent models
Considering that drug injection and action in each pregnant female represent the biggest experimental variables in such a study we examined cohorts of mice obtained from significant numbers of treated and control dams (n = 13 VPA dams and 15 vehicle dams, >30 offspring per condition analyzed)
VPA treatment of cultured neurons during the early developing phase (DIV0-6) resulted in a more severe reduction of GAD65 expression (41.5%+/−3 .8 reduction) as compared to treatment at a later stage (DIV9–15) (22.0%+/−1.7 reduction) (Fig. 3f). These findings indicate that the dysregulation of synaptic proteins observed after in utero VPA-exposure can be replicated by direct VPA treatment of cultured neurons

Summary

Introduction

The impact of in utero VPA exposure has been explored in rodent models. Administration of VPA to pregnant rats or mice during the third trimester results in molecular, synaptic and behavioral alterations in the offspring. Electrophysiological studies suggest that prenatal VPA exposure in rats leads to enhanced long-term potentiation and local hyper-connectivity through increased synaptic N-methyl-D-aspartic acid (NMDA) receptor density in neocortical areas[11,12,13], increased frequency of mEPSCs in the amygdala[14], and impaired cortical inhibitory synaptic transmission[15]. The mechanisms underlying these alterations are still far from being understood.

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