Chronic prenatal exposure to ethanol can lead to a spectrum of teratogenic outcomes that are classified in humans as Fetal Alcohol Spectrum Disorders (FASD). One of the most prevalent and persistent neurocognitive components of FASD is attention deficits, and it is now thought that these attention deficits differ from traditional Attention Deficit Hyperactivity Disorder (ADHD) in their quality and response to medication. However, the neuronal mechanisms underlying attention deficits in FASD are not well understood. We show here that following developmental binge-pattern ethanol exposure, adult mice exhibit impaired performance on the five-choice serial reaction time test for visual attention, with lower accuracy during initial training and a higher rate of omissions under challenging conditions of high attention demand. Whole-cell electrophysiology experiments in these same mice find dysregulated pyramidal neurons within layer VI of the medial prefrontal cortex, which are critical for normal attention performance. Layer VI neurons show decreased intrinsic excitability and increased responses to stimulation of both nicotinic acetylcholine receptors and AMPA glutamate receptors. Moreover, although nicotinic acetylcholine responses correlate with performance on the five-choice task in control mice, these relationships are completely disrupted in mice exposed to ethanol during development. These findings demonstrate a novel outcome of developmental binge-pattern ethanol exposure and suggest that persistent alterations to the function of prefrontal layer VI neurons play an important mechanistic role in attention deficits associated with FASD.
Significance Statement: Children who exhibit Fetal Alcohol Spectrum Disorders (FASD) are often diagnosed with co-morbid Attention Deficit Hyperactivity Disorder (ADHD), even though mechanisms underlying attention deficits in these two disorders are now believed to differ. We show in mice following developmental binge-pattern ethanol exposure that deficits on an attention task are accompanied by dysregulated function of prefrontal cortex layer VI pyramidal neurons, which are known to be critical for normal attention. These layer VI neurons show decreased intrinsic excitability and increased responses to excitatory neurotransmission, and relationships between their nicotinic signaling and attention performance are disrupted. These findings demonstrate novel mechanisms and potential therapeutic targets to mitigate attention deficits associated with FASD.
The authors declare no competing financial interests.
The Banting Research Foundation; Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (NSERC) .