23.3 TARGETING GENETIC AND ENVIRONMENTAL RISK FOR MENTAL ILLNESS IN THE WOMB

Abstract

Background: Complex diseases, including mental illnesses, are the result of interactions between genetic and environmental factors. Maternal illness, smoking, nutritional deficits, psychosocial stress, and psychiatric symptoms during pregnancy are examples of environmental factors associated with increased risk for later mental illness, including schizophrenia, in offspring; pathophysiology in cholinergic mechanisms involved in inhibitory neurocircuit functioning is a demonstrated heritable defect in adults with schizophrenia and their families. Cholinergic mechanisms also have an important role in early brain development. CHRNA7 and its receptor product, the a7-nicotinic acetylcholine receptor, are expressed at significantly higher levels in fetuses compared to adults or children, and a7-nicotinic receptors are more widely dispersed in fetal brain. Since cholinergic innervation does not reach the cerebrum until near birth, a7-nicotinic receptors are activated by choline present in the amniotic fluid during fetal development. There is additional high fetal demand for choline for the membrane phospholipids required for fetal growth. Together these demands can overwhelm the mother's ability to supply fetal needs through synthesis and dietary intake, particularly in the presence of other environmental challenges. We propose that schizophrenia-associated inhibitory neurocircuit dysfunction occurs as a result of an interaction between α7 nicotinic receptor density and choline availability during fetal brain development and provides a target intervention/prevention strategy. Methods: Inhibitory neurocircuit dysfunction is related to auditory cerebral inhibition deficits assessed using a paired-click paradigm. Each click elicits a preattentive event-related brain response (P50) that occurs approximately 50 msec (∼ 75 msec in infants) after presentation. Reductions in amplitudes of the response to the second click by at least 50% compared to the response to the first click indicates intact cerebral inhibition. Our previous studies have shown that cerebral inhibition is developed at birth, stable over first 4 years of life, and diminished in infants of mothers who smoked during pregnancy and in infants of parents with major mental illness. Results: In a double-blind placebo control trial of 100 pregnant mothers, participants either received 6300 mg of phosphatidylcholine (900 mg choline) or corn oil. Until approximately 3 months of age, infants received 600 mg of phosphatidylcholine (100 mg choline) or placebo once daily in an oral suspension. At 4 weeks of age, infants of mothers in the supplemented group had better cerebral inhibition than those in the placebo group. Supplementation also improved cerebral inhibition in infants with an increased genetic risk associated with reduced receptor density. Cerebral inhibition at 4 weeks also predicted 40-month attention and withdrawal ratings on the Child Behavior Checklist 1 5. In an observational study of 162 pregnant women, free serum choline levels at 16 weeks gestation were associated with improved cerebral inhibition in infants at 4 weeks and appeared to protect neurocircuit development in infants of mothers who 1) developed infection during pregnancy, 2) had elevated depression ratings during pregnancy, or 3) used marijuana during pregnancy. Behaviorally, higher maternal serum choline levels were associated with higher Orientation/Regulation scores on the Infant Behavior Questionnaire-R at 12 months of age. Conclusions: In human pregnancy, perinatal choline supplementation enhances the development of cerebral inhibition, rescues genetically vulnerable individuals, and improves behavioral outcomes.