Neurodevelopmental Effects of Gestational Gabapentin Exposure - Project Summary Antiseizure medications (ASMs) are teratogens and are one of the most commonly prescribed teratogens to women of childbearing potential (WCP). Above and beyond congential malformations, many ASMs lead to impairments in neurodevelopment such as reduced IQ and increased risk of autism. In addition to their use in epilepsy, ASMs are used for a variety of indications (e.g., epilepsy, pain, psychiatric) exposing a large number of WCP. However, the risks to the fetus remain uncertain for the large majority of ASMs, limiting the ability of clinicians to adequately advise WCP. Gabapentin is one of the most commonly prescribed medications in the USA and it is one of the most commonly prescribed ASMs in WCP and in pregnancy. Gabapentin antagonizes thrombospondin powerfully inhibiting excitatory synapse formation at therapeutic concentrations. Exposure of immature animal brains to gabapentin results in reduced excitatory synapses in the cerebral cortex. However, standard animal models to determine the functional consequences of this action have not been studied, dose- response curves are unknown, and other mechanisms of drug effects on the immature brain have not been studied. Despite its common use in pregnancy, its risks to the fetus remain uncertain because we have inadequate data on neurodevelopmental effects of fetal gabapentin exposure. The purpose of our study is to address these gaps in knowledge. To address this gap, we will determine the neurodevelopmental impact of fetal exposure to gabapentin in a rat model. We will assess dose dependence (3 dose levels) and exposure timing (4 exposure windows) on behavior, synaptic development and neurophysiology, brain structure, and transcriptomic changes. In Aim 1, we will test the hypothesis that GBP will produce dose- and gestational-age-dependent neurobehavioral deficits. We will examine reflex ontogeny, sensory and motor function, social, anxiety-like, and appetitive behaviors, and learning/memory. In Aim 2, we will test the hypothesis that GBP will induce dose- and gestational-age-dependent alterations in excitatory synaptic development and subsequent hippocampal circuit function. Through whole-cell patch clamp recordings we will assess functional synaptic development at two post- treatment time points through excitatory and inhibitory post-synaptic current frequency. We will, at the same time points, evaluate hippocampal long term potentiation as a test of circuit function, and a key contributor to the memory domains tested in Aim 1. In Aim 3, we will test the hypothesis that GBP will induce dose- and gestational- age-dependent alterations in (A) the hippocampal transcriptome as assed by bulk RNAseq and (B) grey and white matter volume, and white matter integrity as assessed by high resolution MRI. Together these data will provide a knowledge base to help inform clinical practice by providing an evidence base for risks related to fetal gabapentin exposure, and thus impact therapeutic decisions in WCP.
