Valproate-Induced Neurodevelopmental Deficits inXenopus laevisTadpoles

Abstract

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

“…Here, we first tested whether MSI was also present in tadpole behavioral responses, and whether this behavior was consistent with inverse effectiveness. In Xenopus tadpoles, visually guided behavior and acoustically driven startles are well characterized, and ideal for testing MSI (Figure 1A) (Khakhalin et al, 2014; James et al, 2015; Truszkowski et al, 2016). Tadpoles change their swimming speed (in cm/s) when presented with a visual counterfacing grating in a manner directly proportional to the contrast of the grating (Figure 1B, Visual: 0%: 3.22 ± 0.25; 25%: 3.29 ± 0.36; 50%: 3.7 ± 0.51, 100%: 4.76 ± 0.53) (Schwartz et al, 2011).…”

Pentylenetetrazole-induced seizures in developing rats prenatally exposed to valproic acid

“…These authors suggest that exposure to VPA at this embryonic stage produces a reduced inhibitory function of the brain similar to autistic patients (Kim et al, 2011). A recent study also demonstrated that Xenopus laevis tadpoles exposed to VPA have increased PTZ-induced seizure susceptibility, which was associated with hyperconnected neural networks in the optic tectum, an increased excitatory and inhibitory synaptic drive and elevated levels of spontaneous synaptic activity (James et al, 2015). Our results also showed that the seizure severity is reduced in the VPA- subgroup.…”

Emergence of Selectivity to Looming Stimuli in a Spiking Network Model of the Optic Tectum

“…A practical interpretation of ST values is therefore similar to that for SR: for ST = 0 all recurrent connections were eliminated, while for ST = 1 recurrent connections were obviously exaggerated, suggesting that the unknown “realistic” value of ST would lie somewhere in the [0, 1] region. For Figures 2, 3 we used values of SR = ST = 0.5, which produced visual responses similar to that in Khakhalin et al (2014), and spontaneous recurrent events similar in strength to spontaneous barrages in James et al (2015). For hyperparameter search in Figures 4–6, the values of SR and ST were sampled between 0 and 1 in steps of 0.1.…”

“…It is known that principal neurons in the tectum receive strong recurrent excitation (Pratt et al, 2008; Liu et al, 2016) that supports spontaneous neuronal activity during development (Pratt and Aizenman, 2007; Imaizumi et al, 2013; James et al, 2015). Principal tectal neurons also demonstrate prominent and rapid inactivation of spiking (Aizenman et al, 2003; Ciarleglio et al, 2015), which allowed us to suggest that together these two phenomena may underlie, or at least contribute to collision detection (Khakhalin et al, 2014).…”