Long-term improvements in sensory inhibition with gestational choline supplementation linked to α7 nicotinic receptors through studies in Chrna7 null mutation mice

Abstract

Perinatal choline supplementation has produced several benefits in rodent models, from improved learning and memory to protection from the behavioral effects of fetal alcohol exposure. We have shown that supplemented choline through gestation and lactation produces long-term improvement in deficient sensory inhibition in DBA/2 mice which models a similar deficit in schizophrenia patients. The present study extends that research by feeding normal or supplemented choline diets to DBA/2 mice carrying the null mutation for the α7 nicotinic receptor gene (Chrna7). DBA/2 mice heterozygotic for Chrna7 were bred together. Dams were placed on supplemented (5 gm/kg diet) or normal (1.1 gm/kg diet) choline at mating and remained on the specific diet until offspring weaning. Thereafter, offspring were fed standard rodent chow. Adult offspring were assessed for sensory inhibition. Brains were obtained to ascertain hippocampal α7 nicotinic receptor levels. Choline-supplemented mice heterozygotic or null-mutant for Chrna7 failed to show improvement in sensory inhibition. Only wildtype choline-supplemented mice showed improvement with the effect solely through a decrease in test amplitude. This supports the hypothesis that gestational-choline supplementation is acting through the α7 nicotinic receptor to improve sensory inhibition. Although there was a significant gene-dose-related change in hippocampal α7 receptor numbers, binding studies did not reveal any choline-dose-related change in binding in any hippocampal region, the interaction being driven by a significant genotype main effect (wildtype>heterozygote>null mutant). These data parallel a human study wherein the offspring of pregnant women receiving choline supplementation during gestation, showed better sensory inhibition than offspring of women on placebo.

Perinatal Phosphatidylcholine Supplementation and Early Childhood Behavior Problems: Evidence for CHRNA7 Moderation

“…A similar analysis was performed in a previous study in 50 children who were recorded as newborns but were not in the intervention trial (38). That study found significant effects of newborn P50 S2/S1 ratio on 40-month Child Behavior Checklist ratings for total problems and the anxious/depressed and attention subscales.…”

“…In animal models, α7-nicotinic receptor activation is required for the effect of choline on inhibitory neurotransmission. In vitro, tissues derived from Chrna7 null mouse mutants do not show prenatal conversion of chloride transporter and development of inhibition; in vivo, Chrna7 null mutants do not respond to perinatal choline treatments with increased inhibition of the murine analog of human P50 responses (37, 38). A similar definitive test of the specific action of choline on α7-nicotinic receptors is not possible in humans.…”

Elevated kynurenine pathway metabolism during neurodevelopment: Implications for brain and behavior

“…The benefits of choline-supplementation include long-term improvements in sensory inhibition (Stevens et al, 2008, 2014), as well as attenuation of either in utero stress exposure (Schulz et al, 2014) or maternal immune activation (Wu et al, 2015) on both anxiety- and cognitive-related behaviors in adulthood. A recent study extended this research by feeding normal and supplemented choline diets, perinatally, to mice carrying the null mutation for the α7nACh receptor gene ( Chrna7 ) and demonstrated that the Chrna7 null-mutant failed to show behavioral improvements with choline-supplementation, strongly implicating functional α7nACh receptors as the mechanism (Stevens et al, 2014). However, additional mechanisms working in parallel with α7nACh receptor stimulation should be considered, including changes in gene expression, particularly DNA methylation, noted after choline supplementation during development (reviewed in Blusztajn and Mellott, 2012).…”

Sex differences in animal models of schizophrenia shed light on the underlying pathophysiology

“…α7-nicotinic acetylcholine receptor knockout mice (α7-nAChR KO) show deficits in sensory inhibition, working memory and attention, as well as reduced cortical expression levels of parvalbumin and NMDAR at adulthood(Fernandes et al 2006;Young et al 2007;Adams et al 2008). From 10 original manuscripts assessing this model, seven included males only, and two reported no sex differences, although limited sample sizes were used(Young et al 2011;Stevens et al 2014). In a molecular study by Adams and Stevens, male but not female α7-nAChR het mice showed reduced hippocampal GABA(A) receptor expression(Adams et al 2012).…”