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Distinct Defects in Synaptic Differentiation of Neocortical Neurons in Response to Prenatal Valproate Exposure
Yoko Iijima1, Katharina Behr2, Takatoshi Iijima1
1Biozentrum, University of Basel, Klingelbergstrasse 50-70, 4056 Basel, Switzerland.
Insights
Prenatal exposure to valproic acid (VPA) in mice alters brain development, increasing autism spectrum disorder (ASD) risk. This study reveals epigenetic changes in synaptic function, offering insights into ASD pathophysiology.
Area of Science:
- Neuroscience
- Developmental Biology
- Epigenetics
Background:
- Autism spectrum disorders (ASDs) are neurodevelopmental conditions impacting social interaction and behavior.
- Prenatal exposure to valproic acid (VPA), an epilepsy and bipolar disorder medication, is a known risk factor for ASD.
- Rodent models of in utero VPA exposure are crucial for investigating ASD-related synaptic pathophysiology.
Purpose of the Study:
- To identify synaptic protein alterations contributing to autism-related behaviors in offspring exposed to VPA in utero.
- To determine if VPA exposure in cultured neurons replicates in vivo molecular changes.
- To elucidate the epigenetic mechanisms underlying VPA-induced synaptic alterations in an ASD model.
Main Methods:
- Systematic analysis of synaptic proteins in mice offspring following in utero VPA exposure.
- In vitro study of VPA effects on cultured neocortical neurons.
- Assessment of excitatory/inhibitory synaptic balance and neuronal network activity.
- Pharmacological investigation of histone deacetylase inhibition.
Main Results:
- VPA-exposed neurons showed an increased number of glutamatergic synapses and a decreased number of GABAergic synapses.
- This shift in synaptic balance led to significantly increased spontaneous neuronal activity.
- Inhibition of histone deacetylases was identified as a primary mechanism driving these synaptic alterations.
Conclusions:
- In utero VPA exposure induces significant synaptic and network alterations in the developing brain, modeling aspects of ASD.
- Epigenetic modifications, specifically histone deacetylase inhibition, play a critical role in VPA's teratogenic effects on synaptic development.
- This research highlights a potential epigenetic pathway contributing to the synaptic pathophysiology observed in an ASD mouse model.
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.
