Exploring the complexity of intellectual disability in fetal alcohol spectrum disorders.

Brain development in mammals is long lasting. It begins early during embryonic growth and is finalized in early adulthood. This progression represents a delicate choreography of molecular, cellular, and physiological processes initiated and directed by the fetal genotype in close interaction with environment. Not surprisingly, most aberrations in brain functioning including intellectual disability (ID) are attributed to either gene(s), or environment or the interaction of the two. The ensuing complexity has made the assessment of this choreography, ever challenging. A model to assess this complexity has used a mouse model (C57BL/6J or B6) that is subjected to prenatal alcohol exposure. The resulting pups show learning and memory deficits similar to patients with fetal alcohol spectrum disorder (FASD), which is associated with life-long changes in gene expression. Interestingly, this change in gene expression underlies epigenetic processes including DNA methylation and miRNAs. This paradigm is applicable to ethanol exposure at different developmental times (binge at trimesters 1, 2, and 3 as well as continuous preference drinking (70%) of 10% alcohol by B6 females during pregnancy). The exposure leads to life-long changes in neural epigenetic marks, gene expression, and a variety of defects in neurodevelopment and CNS function. We argue that this cascade may be reversed postnatally via drugs, chemicals, and environment including maternal care. Such conclusions are supported by two sets of results. First, antipsychotic drugs that are used to treat ID including psychosis function via changes in DNA methylation, a major epigenetic mark. Second, post-natal environment may improve (with enriched environments) or worsen (with negative and maternal separation stress) the cognitive ability of pups that were prenatally exposed to ethanol as well as their matched controls. In this review, we will discuss operational epigenetic mechanisms involved in the development of intellectual ability/disability in response to alcohol during prenatal or post-natal development. In doing so, we will explore the potential of epigenetic manipulation in the treatment of FASD and related disorders implicated in ID.