Developmental windows for effects of choline and folate on excitatory and inhibitory neurotransmission during human gestation

Abstract

Choline and folate are critical nutrients for fetal brain development, but the timing of their influence during gestation has not been previously characterized. At different periods during gestation, choline stimulation of α7-nicotinic receptors facilitates the conversion of γ-aminobutyric acid (GABA) receptors from excitatory to inhibitory and recruitment of GluR1-R2 receptors for faster excitatory responses to glutamate. The outcome of the fetal development of inhibition and excitation was assessed in 159 newborns by P50 cerebral auditory-evoked responses. Paired stimuli, S1 and S2, were presented 500 ms apart. Higher P50 amplitude in response to S1 (P50_S1microV) assesses excitation, and lower P50_S2microV assesses inhibition in this paired-stimulus paradigm. The development of inhibition was related solely to maternal choline plasma concentration and folate supplementation at 16 weeks’ gestation. The development of excitation was related only to maternal choline at 28 weeks. Higher maternal choline concentrations later in gestation did not compensate for earlier lower concentrations. At 4 years of age, increased behavior problems on the Child Behavior Checklist 1.5–5 years were related to both newborn inhibition and excitation. The incomplete development of inhibition and excitation associated with lower choline and folate during relatively brief periods of gestation thus has enduring effects on child development.