Effects of Prenatal Alcohol Exposure on Alzheimer's Disease-associated Neuropsychiatric Symptoms

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PROJECT SUMMARY / ABSTRACT Alzheimer’s disease (AD) is the most common cause of dementia, affecting 3–11% of the United States elderly. On the other hand, the estimated incidence of prenatal alcohol exposure (PAE)-induced mental disability or disease is 10 per 1000 live births. Although theoretically PAE-induced mental diseases are preventable, the prevalence of PAE has been reported to be as high as 10%-16.3%. Among a broad spectrum of PAE and AD- associated symptoms, progressive impairment of cognition has been extensively investigated. However, limited symptomatic relief in these patients by available medications demonstrates lack of understanding of the neuronal substrates, especially the PAE and/or AD-associated neuropsychiatric symptoms (NPSs). It is well accepted that apathy, the top ranked NPS in both PAE and AD, arises through interactions between genetic and environmental factors. PAE has been considered an environmental insult to the brain and AD high risk genes have been identified as top genetic factors facilitating the onset of NPSs. Together with the increased life expectancy by 8-10 years in the USA in the last 50 years, the evaluation of interactions between PAE history and AD high-risk genes at the molecular, synaptic, circuit, and behavioral levels is highly urgent. Our awarded parent R01 grant focused on exploring changes of excitatory synaptic transmission to the nucleus accumbens (NAc) underlying the synaptic loss and the low motivation phenotype in subjects with high risk of AD and a history of PAE. Besides the synaptic transmission, evaluation of a brain region’s functional output is directly related to the excitability of the projecting neurons in that region. Thus, in this Administrative Supplement proposal as a response to PA-18-591, we will focus on the excitability-related readouts, including the number of action potentials measured by whole-cell patch clamp and the calcium transient activity measured in vivo and ex vivo.