Prenatal ethanol exposure results in cell-type, age, and sex-dependent differences in the neonatal striatum that coincide with early motor deficits.

Abstract

Delayed motor development is an early clinical sign of Fetal Alcohol Spectrum Disorders (FASD). However, changes at the neural circuit level that underlie early motor differences are underexplored. The striatum, the principal input nucleus of the basal ganglia, plays an important role in motor learning in adult animals, and the maturation of the striatal circuit has been associated with the development of early motor behaviors. Here, we briefly exposed pregnant C57BL/6 dams to ethanol (5% w/w) in a liquid diet on embryonic days (E)13.5-16.5, and assessed the mouse progeny using a series of 9 brief motor behavior tasks on postnatal days (P)2-14. Live brain slices were then obtained from behaviorally-tested mice for whole cell-voltage and current clamp electrophysiology to assess GABAergic/glutamatergic synaptic activity, and passive/active properties in two populations of striatal neurons: GABAergic interneurons and spiny striatal projection neurons. Electrophysiologically-recorded spiny striatal projection neurons were also filled intracellularly with biocytin for post-hoc analysis of dendritic morphology. We found that prenatal ethanol exposure resulted in developmental motor delays that were more severe in male mice and coincided with sex-dependent differences in the maturation of striatal neurons. Our findings indicate that prenatal ethanol exposure results in dynamic morphological and functional changes to the developmental trajectories of striatal neurons commensurate with the development of motor behaviors that differ between male and female mice.Significance Statement Developmental differences in motor behaviors are an early clinical sign of Fetal Alcohol Spectrum Disorders (FASD) but the neural circuit level changes that contribute to these differences have not yet been determined. Here we demonstrate that a brief binge exposure to ethanol alters the motor development of neonatal mice in a sex-dependent manner, and identify concurrent differences in the functional, synaptic and morphological development of striatal GABAergic interneurons and medium spiny striatal projection neurons. These data suggest that altered development of striatal neurons may contribute to differences in early motor development observed in individuals with FASD.