Long-Lasting Neural Circuit Dysfunction Following Developmental Ethanol Exposure

Abstract

Fetal Alcohol Spectrum Disorder (FASD) is a general diagnosis for those exhibiting long-lasting neurobehavioral and cognitive deficiencies as a result of fetal alcohol exposure. It is among the most common causes of mental deficits today. Those impacted are left to rely on advances in our understanding of the nature of early alcohol-induced disorders toward human therapies. Research findings over the last decade have developed a model where ethanol-induced neurodegeneration impacts early neural circuit development, thereby perpetuating subsequent integration and plasticity in vulnerable brain regions. Here we review our current knowledge of FASD neuropathology based on discoveries of long-lasting neurophysiological effects of acute developmental ethanol exposure in animal models. We discuss the important balance between synaptic excitation and inhibition in normal neural network function, and relate the significance of that balance to human FASD as well as related disease states. Finally, we postulate that excitation/inhibition imbalance caused by early ethanol-induced neurodegeneration results in perturbed local and regional network signaling and therefore neurobehavioral pathology.

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

“…GABA is known to be a critical modulator of brain development, and its reduction during critical periods alters normal development of cortical circuits (Le Magueresse & Monyer, 2013). In the adult, reduced GABA neurotransmission is thought to contribute to hyperexcitability and disrupted cortical oscillations that have been noted in various developmental disorders (Sadrian et al, 2013). Our findings that several gross features of cortex, such as thickness and laminar organization, are largely normal in the adult animal, is consistent with previous observations that the cortex has substantial capacity to overcome perinatal disruption.…”

“…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, Wilson, & Saito, 2013; Wilson, Peterson, Basavaraj, & Saito, 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).…”

“…More detailed examinations found evidence of altered dendritic length and spine density (Berman & Hannigan, 2000; Cui et al, 2010; Lawrence, Otero, & Kelly, 2012; Susick, Lowing, Provenzano, Hildebrandt, & Conti, 2014), and found evidence of disrupted organization of cortical sensory areas (Margret et al, 2006; Medina, Krahe, & Ramoa, 2005; Miller & 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, Lopez-Guzman, Wilson, & Saito, 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.…”

“…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, 2014). The findings suggest that deficits of GABAergic inhibition may cause a characteristic profile of electrophysiological deficits.…”