Valproate-induced neurodevelopmental deficits in Xenopus laevis tadpoles.

Autism spectrum disorder (ASD) is increasingly thought to result from low-level deficits in synaptic development and neural circuit formation that cascade into more complex cognitive symptoms. However, the link between synaptic dysfunction and behavior is not well understood. By comparing the effects of abnormal circuit formation and behavioral outcomes across different species, it should be possible to pinpoint the conserved fundamental processes that result in disease. Here we use a novel model for neurodevelopmental disorders in which we expose Xenopus laevis tadpoles to valproic acid (VPA) during a critical time point in brain development at which neurogenesis and neural circuit formation required for sensory processing are occurring. VPA is a commonly prescribed antiepileptic drug with known teratogenic effects. In utero exposure to VPA in humans or rodents results in a higher incidence of ASD or ASD-like behavior later in life. We find that tadpoles exposed to VPA have abnormal sensorimotor and schooling behavior that is accompanied by hyperconnected neural networks in the optic tectum, increased excitatory and inhibitory synaptic drive, elevated levels of spontaneous synaptic activity, and decreased neuronal intrinsic excitability. Consistent with these findings, VPA-treated tadpoles also have increased seizure susceptibility and decreased acoustic startle habituation. These findings indicate that the effects of VPA are remarkably conserved across vertebrate species and that changes in neural circuitry resulting from abnormal developmental pruning can cascade into higher-level behavioral deficits.

A cellular mechanism for inverse effectiveness in multisensory integration.

To build a coherent view of the external world, an organism needs to integrate multiple types of sensory information from different sources, a process known as multisensory integration (MSI). Previously, we showed that the temporal dependence of MSI in the optic tectum of Xenopus laevis tadpoles is mediated by the network dynamics of the recruitment of local inhibition by sensory input (Felch et al., 2016). This was one of the first cellular-level mechanisms described for MSI. Here, we expand this cellular level view of MSI by focusing on the principle of inverse effectiveness, another central feature of MSI stating that the amount of multisensory enhancement observed inversely depends on the size of unisensory responses. We show that non-linear summation of crossmodal synaptic responses, mediated by NMDA-type glutamate receptor (NMDARs) activation, form the cellular basis for inverse effectiveness, both at the cellular and behavioral levels.