Periconceptional folate deficiency leads to autism-like traits in Wistar rat offspring

Abstract

Background: Folates in their role as key one carbon donors, are essential for two major pathways: the synthesis of DNA and RNA precursors and DNA methylation. A growing body of evidence from epidemiological studies indicates a possible association between nutritional and functional deficiency in folates and Autism Spectrum Disorders (ASD). However, there are no available behavioral animal studies on periconceptional one‑carbon donor deficiency during gestation and the autistic phenotype.

Objective: The objective of this study was to determine if the periconceptional alteration of one‑carbon metabolism induced with a folate deficient diet would affect the behaviour of rat offspring.

Methods: Female Wistar rats were divided in two groups: control (basal diet, in compliance with standards of regular laboratory diets), or exposed during one month before breeding until Gestational Day 15 to a modified diet with no added folic acid (0.2mg/kg of food), reduced choline (750mg/kg of food), and added 1% SST (a non-absorbable antibiotic used to inhibit folate synthesis by gut bacteria). We administered behavioral tests to offspring, i.e., open field (P20), social interactions (P25), marble burying (P30), elevated plus maze (P35), and prepulse inhibition of the acoustic startle reflex (sensorimotor gating) (P45). Blood homocysteine levels were used to confirm the deficit in one‑carbon donors.

Results: Compared to controls, offspring with the periconceptional deficit in folate showed: (i) congenital body malformations; (ii) reduced social interactions, with a ~30% decrease in social sniffing behavior; (iii) reduced exploration of the open arm by 50% in the elevated plus maze test, indicating increased anxiety; (iv) a ~160% increased number of marbles buried, indicating repetitive behaviors; and (v) altered sensorimotor gating, with a global 50% decrease in startle inhibition.

Conclusion: Maternal periconceptional deficit in folate provokes alterations in the behavior of offspring relevant to the autistic-like phenotype.

Keywords: Autism Spectrum Disorders; Behavior; Folate; One‑carbon metabolism; Rat.