Chronic Gestational Exposure to Ethanol Leads to Enduring Aberrances in Cortical Form and Function in the Medial Prefrontal Cortex

Abstract

Background Exposure to ethanol in utero alters the disposition of tangentially migrating GABAergic interneurons in the fetal brain. The medial ganglionic eminence (MGE) gives rise to a large portion of cortical GABAergic interneurons, including the parvalbumin-expressing interneurons that shape and contribute to inhibitory/excitatory (I/E) balance of the intracortical circuit. Here, we investigated in the mouse medial prefrontal cortex (mPFC) the hypothesis that low levels of maternal ethanol consumption from closure of the neural tube embryonic day(E) 9.5 until birth, results in an enduring interneuronopathy. Methods Pregnant mice were subjected to a 2% w/w ethanol consumption regimen starting at neural tube closure and ending at parturition. Neurogenesis in the MGE was assessed by BrdU-immunofluorescence at E12.5. The count and distribution of parvalbumin-expressing interneurons were determined in adult animals, and patch clamp electrophysiology was performed to determine GABAergic function and I/E balance. Open field behavior in adult mice was assessed to determine whether the ethanol-exposed cohort displayed a lasting alteration in exploratory behavior. Results In embryos exposed to ethanol in utero, we found increased BrdU labeling in the MGE, pointing to increased neurogenesis. Adult mice prenatally exposed to ethanol were hyperactive, and this was associated with an increase in parvalbumin-expressing GABAergic interneurons in the mPFC. In addition, prenatal ethanol exposure altered the balance between spontaneous inhibitory and excitatory synaptic input and attenuated GABAergic tone in layer V mPFC pyramidal neurons in juvenile mice. Conclusion These findings underscore that altered migration of GABAergic interneurons contributes to the ethanol-induced aberration of cortical development and that these effects persist into adulthood as altered cortical form and function.

The role of IL-6 in neurodevelopment after prenatal stress

“…Understanding other maternal physiological challenges (e.g. prenatal ethanol exposure, metabolic or psychosocial stress) will also elucidate additional offspring neurodevelopmental changes of interest (Brunton and Russell, 2010; Krakowiak et al, 2012; Skorput and Yeh, 2016). Many maternal manipulations, even with diffusible factors, alter cardiovascular function and other nonspecific physiology, which may play a role in offspring changes.…”

Strain-specific programming of prenatal ethanol exposure across generations

“…The cerebral cortex is of major importance to this behavior, as it plays a critical role in motor coordination (Donchin et al, 1998, Carlson et al, 2013, Gigante et al, 2014, Carter et al, 2016). The prenatal developmental process of the cerebral cortex is susceptible to PAE-induced disruptions that can last long into adulthood, especially when exposure occurs during late gestation (Miller, 1996, Skorput and Yeh, 2016, Miller, 1986). Therefore, assessing PAE-induced changes in the cerebral cortex may provide valuable insight into changes in motor coordination under the influence of ethanol, such as those previously reported in Sprague Dawley rats (Nizhnikov et al, 2016).…”

Neonatal alcohol exposure reduces number of parvalbumin-positive interneurons in the medial prefrontal cortex and impairs passive avoidance acquisition in mice deficits not rescued from exercise

“…Although a few studies suggest neonatal alcohol exposure can either increase or have no impact on the number of PV+ interneurons (Mitchell et al, 2000, Skorput and Yeh, 2016), the current data add to a growing literature that shows a negative influence of neonatal alcohol exposure on PV+ interneurons (Moore et al, 1998, Coleman et al, 2009, Smiley et al, 2015). PD 7 ethanol treatment has been shown to result in over a 30% reduction in the number of PV+ interneurons in the cerebral cortex when measured in adulthood (Smiley et al, 2015) and rat pups born to dams fed an ethanol-containing liquid diet throughout gestation exhibit 45% fewer PV+ interneurons in the ACC in the absence of changes in structure volume on PD 60 (Moore et al, 1998).…”