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 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, S2, were presented 500 msec apart. Higher P50 amplitude in response to S1 (P50_S1microV) assesses excitation, and lower P50_S2microV assesses inhibition in this paired-stimulus paradigm. Development of inhibition was related solely to maternal choline plasma concentration and folate supplementation at 16 weeks' gestation. 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 1½-5yrs were related to both newborn inhibition and excitation. 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.

Keywords: Attention; Brain; Choline; Evoked Potentials Auditory; Excitation; Fetal Development; Hippocampus; Human; Inhibition; Phosphatidylcholine; Pregnancy.

Figure 1.

P50 auditory evoked potentials recorded from a female infant at 4 (top) and 13 weeks (bottom) after birth to stimulus S1 (left) and S2 (right). Recordings are the averaged response to 85 stimulus pairs. P50_S1 amplitudes were measured from the positive peak between 50 to 100 msec latency from the stimulus to the preceding negativity, because of the longer latency of the P50 response in infants. P50_S2 amplitudes were measured from the largest positive peak within 15 msec of the latency of P50_S1. Actual latency in these recordings was 69-81msec. P50 amplitude increased during development: P50_S1 2.32microV at 4 weeks and 5.65microV at 13 weeks. However the ratio of P50_S2microV to P50_S1microV, a measure of cerebral inhibition, remained constant: 0.35 at 4 weeks and 0.36 at 13 weeks. Vertical axis is microV and horizontal axis is msec. The stimulus was delivered at time 0.

Figure 2.

Top: Relationship between P50_S2microV adjusted for P50_S1microV and 16-gestational-week maternal plasma choline, β = −0.156, P = 0.044, for 159 1-month-old newborns. Bottom: Relationship between P50_S1microV and 28-gestational-week maternal plasma choline, β = 0.237, P = 0.003.

Figure 3.

Maternal choline concentrations were related to newborn P50_S2microV covaried for P50_S1microV, F_df3,151 = 3.688, P = 0.013. Prenatal vitamin with folate use interacted with choline concentrations, F_df3,151 = 3.333, P = 0.021. Gestational age at birth was a covariate in the analysis, but not significant.