Selective reduction of cerebral cortex GABA neurons in a late gestation model of fetal alcohol spectrum disorder

Abstract

Fetal alcohol spectrum disorders (FASD) are associated with cognitive and behavioral deficits, and decreased volume of the whole brain and cerebral cortex. Rodent models have shown that early postnatal treatments, which mimic ethanol toxicity in the third trimester of human pregnancy, acutely induce widespread apoptotic neuronal degeneration and permanent behavioral deficits. However, the lasting cellular and anatomical effects of early ethanol treatments are still incompletely understood. This study examined changes in neocortex volume, thickness, and cellular organization that persist in adult mice after postnatal day 7 (P7) ethanol treatment. Post mortem brain volumes, measured by both MRI within the skull and by fluid displacement of isolated brains, were reduced 10–13% by ethanol treatment. The cerebral cortex showed a similar reduction (12%) caused mainly by lower surface area (9%). In spite of these large changes, several features of cortical organization showed little evidence of change, including cortical thickness, overall neuron size, and laminar organization. Estimates of total neuron number showed a trend level reduction of about 8%, due mainly to reduced cortical volume but unchanged neuron density. However, counts of calretinin (CR) and parvalbumin (PV) subtypes of GABAergic neurons showed a striking >30% reduction of neuron number. Similar ethanol effects were found in male and female mice, and in C57BL/6By and BALB/cJ mouse strains. Our findings indicate that the cortex has substantial capacity to develop normal cytoarchitectonic organization after early postnatal ethanol toxicity, but there is a selective and persistent reduction of GABA cells that may contribute to the lasting cognitive and behavioral deficits in FASD.

Developmental ethanol exposure-induced sleep fragmentation predicts adult cognitive impairment

“…While the developmental EtOH exposed mice were also behaviorally hyperactive in their homecage, 24hr hyperactivity levels did not correlate with sleep disturbance. Given the important role of sleep in memory consolidation and synaptic plasticity (Durmer and Dinges, 2005, Stickgold and Walker, 2007, Diekelmann and Born, 2010, Abel et al, 2013), the results suggest that developmental EtOH exposure not only induces immediate neural circuit disruption and cell death (Abel and Sokol, 1986, Bonthius and West, 1990, Ikonomidou et al, 2000, Olney et al, 2002a, Olney et al, 2002b, Saito et al, 2007, Gil-Mohapel et al, 2010, Saito et al, 2010, Sadrian et al, 2012, Smiley et al, 2015), but also induces the sustained and repeated insult of sleep deprivation, which in itself can lead to cognitive and emotional impairments (Durmer and Dinges, 2005, Killgore, 2010, LeGates et al, 2014). …”

“…There are a variety of potential mechanisms that could contribute to this sleep dysfunction. For example, previous work has demonstrated that neonatal ethanol exposure in mice severely reduces GABAergic neurons in the cortical regions of adult brains (Sadrian et al, 2014, Smiley et al, 2015), contributing to hyper-excitability of limbic circuits (Wilson et al, 2011, Sadrian et al, 2012), and seizure development (Bonthius et al, 2001, Bell et al, 2010). This induced change in excitation/inhibition balance could modify both plasticity and function of forebrain circuits underlying cognition and emotion (Hensch, 2005, Sadrian et al, 2013).…”

“…Commonly used hypnotics target GABAergic receptors (Manfridi et al, 2001, Walsh et al, 2007, Brickley and Mody, 2012), and insomnia and sleep fragmentation have been associated with impaired GABAergic neuron function in these regions (Lundahl et al, 2007, Kalume et al, 2015). Developmental ethanol exposure results in dysregulation of GABAergic neurons, including the parvalbumin expressing subset, throughout many brain regions (Coleman et al, 2012, Sadrian et al, 2014, Skorput et al, 2015, Smiley et al, 2015), potentially further raising the possibility of sleep dysfunction.…”

Transgenic mice with increased astrocyte expression of IL-6 show altered effects of acute ethanol on synaptic function

“…Interestingly, chronic ethanol exposure/withdrawal reduces the number of neurons that immunostain for PAV (Smiley et al, 2015; Udomuksorn et al, 2011; Vongvatcharanon et al, 2010), increases expression of GFAP (Chiang et al, 1994; Vongvatcharanon et al, 2010), increases EEG gamma power in the CNS (Cheaha et al, 2014), increases NMDAR-mediated synaptic responses (Carpenter-Hyland et al, 2004; Hendricson et al, 2007; Nelson et al, 2005), and reduces Kv4.2 expression (Mulholland et al, 2014). Thus, chronic ethanol exposure/withdrawal can produce some of the same characteristics as observed in ethanol-naïve IL-6 tg mice or CNS cultures chronically treated with IL-6.…”

Proceedings of the 2016 annual meeting of the Fetal Alcohol Spectrum Disorders Study Group

“…A decrease in the number of PV neurons would decrease inhibition, resulting in tissue that is more excitable and prone to seizures (Hsieh et al, 2016). A parallel can be drawn to FASD, since it has been reported that developmental alcohol exposure can lead to an increase in oxidative stress (Brocardo, Gil-Mohapel, & Christie, 2011), a decrease in PV neurons (Smiley et al, 2015), and the development of seizures (Bell et al, 2010; Nicita et al, 2014). …”