Autism is characterized by inappropriate social interactions, deficits in verbal communication and facial expressions, and ritualistic and repetitive behaviors. Recent evidence suggests the gaseous neurotransmitter nitric oxide (NO) may regulate certain behaviors characterized by autism-like symptoms. Inhibition of NO leads to hyper-aggression and excessive mounting which may represent inappropriate social interactions along with ritualistic and persistent behaviors observed in autistic-like symptoms. NO inhibition also decreases social investigation towards a social cue of a novel mouse which may reflect deficits in social communication. Many previous studies inhibited NO through deletion of the gene that codes for the synthetic enzyme or a drug induced inhibition of the synthetic enzyme, however, manipulation of dietary intake of the NO precursor, L-arginine, has not been extensively examined for regulation of these same behaviors. L-arginine is a common amino acid found in multiple foods. In the brain L-arginine is converted into NO by the enzyme neuronal nitric oxide synthase (nNOS). In this study, mice fed a diet consisting of a an L-arginine-depleted, L-arginine-supplemented, or control level of L-arginine underwent a series of tests designed to investigate social behaviors and affective responses. I hypothesized that a diet depleted of arginine would result in hyper-aggressive behaviors illustrated by persistent attacks on an intruder mouse along with a decrease of interactions with a socially-novel mouse. An arginine-deficient diet should also evoke persistent swimming in the Porsolt forced-swim test. Quantification of neurons positively stained for citrulline, a byproduct of NO synthesis, will indicate an overall decrease of nitric oxide activity in the brain of mice fed an arginine-deficient diet. Conversely, a diet fortified with L-arginine will result in behaviors and hormonal levels opposite to those observed in mice fed an arginine depleted diet. If behavioral effects are congruent with autistic-like phenotypes, then investigation towards underlying mechanisms of autism through arginine depletion should be considered. This study may also provide a foundation for studying other disorders characterized by social withdrawal, hyper-aggression, or anxiety.This research was supported by NIH grant 745284.No embarg
