Prenatal alcohol exposure, GABAergic interneuron circuitry, early motor behavior, and the developing striatum

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Project Summary Fetal Alcohol Spectrum Disorders (FASD) are the most common cause of non-genetic neurodevelopmental disability worldwide. Clinical symptoms of FASD can vary, but include facial dysmorphology, cognitive deficits and behavioral abnormalities. The variable clinical presentation of FASD makes diagnosis a challenge. Delayed diagnosis is associated with negative clinical outcomes, while early intervention can improve patients’ quality of life. Deficits in gross and fine motor development are some of the earliest identifiable clinical signs of FASD in patients. However, the mechanism by which prenatal alcohol exposure contributes to deficits in early motor skills is not yet known. Functional maturation of neurons within the striatum, the input nucleus of the basal ganglia, is closely associated with onset of complex movements in neonatal mice. The experiments outlined in this F30 proposal will investigate how aberrant development of GABAergic interneuron circuitry within the striatum may relate to developmental motor delays after prenatal alcohol exposure. My preliminary data suggest that prenatal alcohol exposure results in deficient formation of synaptic connections to striatal GABAergic interneurons during the first two postnatal weeks. Specific Aim 1 will leverage whole cell patch clamp electrophysiology, optogenetic and trans-synaptic viral approaches to identify the source of deficits in the formation of functional synaptic afferents to striatal GABAergic interneurons. Specific Aim 2 will establish how observed prenatal alcohol exposure-induced deficits in striatal GABAergic interneuron signaling may relate to altered morphological and functional maturation of striatal projection neurons, and neonatal motor development as measured by a series of brief behavioral tasks assessing the onset of gross, fine, and complex motor abilities during the first two postnatal weeks. This F30 proposal will allow me to fulfill my long-term objective of contributing to a better understanding of the physiological changes underlying the earliest clinical symptoms of FASD in order to improve efforts to identify FASD patients and provide targeted treatment. My goals in completing the proposed work are to develop the intellectual foundations and technical skills necessary to conduct research as physician scientist in the FASD field, with a focus on how prenatal alcohol exposure can affect the development of neural circuits and result in changes in early behaviors.