Selective reduction of cerebral cortex GABA neurons in a late gestation model of fetal alcohol spectrum disorder
Introduction
Fetal alcohol spectrum disorders (FASD) are one of the most common causes of mental disabilities, and affect as many as 1% of children born in the United States (May et al., 2009). Along with cognitive deficits including memory, attention, and sensory perception, FASD is associated with reduced brain volume that persists into adulthood (Bakoyiannis et al., 2014, Norman et al., 2009).
Animal models have been instrumental in providing insights into the brain areas and cellular processes that are affected by FASD. They have demonstrated that the effects of ethanol vary depending on the gestational timing of exposure. Treatment during the rodent early postnatal period, approximating the human third trimester, causes both widespread apoptotic cell death in the brain and long-lasting behavioral deficits (Ikonomidou et al., 2000, Sadrian et al., 2013, Wilson et al., 2011, Wozniak et al., 2004). This is a period when neurogenesis is largely complete, and the brain is rapidly growing (Miller, 1988). Treatments early in this period, around the time of birth in rats, cause pronounced neurodegeneration in hypothalamic and ventral thalamic regions, compared to treatments around P3 that especially affect the dorsal thalamus and hippocampal regions, or treatments around P7 that especially affect cerebral cortex (Ikonomidou et al., 2000). Earlier treatments that model the first and second trimesters of human development also produce anatomical and behavioral changes, although they are somewhat distinct from the late gestational effects (Guerri, 1998, Sadrian et al., 2013). While these earlier ethanol treatments do not cause such widespread apoptosis, they have been shown to disrupt neurogenesis and cell migration (Cuzon, Yeh, Yanagawa, Obata, & Yeh, 2008).
Understanding the enduring effects of FASD on the brain is an area of ongoing research. In human adolescents and adults, FASD causes reduced volumes of gray matter and white matter throughout the forebrain. Gray matter volume reductions as large as 10% have been described across regions of the cerebral cortex, with even larger changes in subcortical structures, including hippocampus and striatum (Coles et al., 2011, Lebel et al., 2012, Nardelli et al., 2011, Norman et al., 2009). Adult animals that were exposed to fetal alcohol typically have a similar profile of volume reductions (Coleman et al., 2012, Leigland et al., 2013). In some models, histological studies showed that these volume reductions corresponded to reduced neuron numbers (Berman and Hannigan, 2000, Ieraci and Herrera, 2007, Miller, 2006, Olney, 2004). More detailed examinations found evidence of altered dendritic length and spine density (Berman and Hannigan, 2000, Cui et al., 2010, Lawrence et al., 2012, Susick et al., 2014), and found evidence of disrupted organization of cortical sensory areas (Margret et al., 2006, Medina et al., 2005, Miller and Potempa, 1990). Additionally, in several cortical and subcortical brain regions there are findings of reduced GABAergic cell density, suggesting that inhibitory circuits in the cerebral cortex may be especially vulnerable to ethanol toxicity (Coleman et al., 2012, Sadrian et al., 2014, Sadrian et al., 2013). At present, it is unclear to what extent these changes are the direct result of cell loss induced by ethanol toxicity, or are secondary effects caused by compensatory brain plasticity that occurs in response to ethanol-induced damage. In particular, inhibition of GABA function in early postnatal development is known to disrupt the normal development of cortical circuits (Le Magueresse & Monyer, 2013).
We recently demonstrated that mouse piriform cortex has reduced PV-immunolabeled GABA cells, along with increased neuron excitability, reduced paired-pulse inhibition, and enhanced oscillatory coherence, caused by ethanol treatment at both early and late gestational stages (Sadrian et al., 2013, Sadrian et al., 2014). The findings suggest that deficits of GABAergic inhibition may cause a characteristic profile of electrophysiological deficits. In the current study, we used a model of late gestational ethanol treatment (mouse P7) to determine whether a similar reduction in GABA cells is present throughout the neocortex, and we measured total neuron number to determine to what extent the neuron reduction was selective for GABAergic neurons. We also evaluated cortical thickness, surface area, and laminar organization, to evaluate the general features of adult cortical disruption caused by perinatal ethanol. Additionally, we included comparisons of C57BL/6By and BALB/cJ strains of mice, as these strains have well-established differences in alcohol preference and are commonly used as genetic animal models in alcohol-related research (Fish et al., 2010, Rodgers and McClearn, 1962, Vadasz et al., 1982, Vadasz et al., 2007).
Section snippets
Subjects and ethanol exposure
Twenty four mice were used, comparing 12 ethanol-treated to 12 saline-treated animals. The two treatment groups were matched to include equal numbers of C57BL/6By and BALB/cJ mice, with equal number of males and females from each strain. Mice were originally obtained from The Jackson Laboratory (Bar Harbor, Maine) in 1978, and maintained by brother × sister mating at the Nathan Kline Institute. Dams and their litters were housed individually in standard mouse cages, and maintained on ad libitum
Whole brain volume and body weight
Whole brain volumes measured by fluid displacement of isolated paraformaldehyde fixed brains were about 13% smaller in ethanol-treated compared to saline-treated mice (p < 0.0001, Table 1). A similar reduction (10%, p < 0.001) was obtained by imaging the brains with MRI before removal from the skull. Ethanol-treated mice also had about 8% reduced body weight (p = 0.015), suggesting that lower brain volume might be caused, at least in part, by decreased body size. However, partial correlation
Discussion
The ethanol treatment used in this study was previously shown to cause widespread cell death across the cerebral cortex within the first few days after treatment (Olney, 2004, Saito et al., 2007, Wilson et al., 2011). The goal of the present study was to determine to what extent the cell loss and cytoarchitectonic disruption caused by this treatment persist in the adult (>P70) neocortex. The findings showed several gross features of cortical organization to be largely unaltered, including
Acknowledgments
This research was supported by NIAAA grant AA023181 and NIMH grant MH086385.
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