Clinical Efficacy of Glutamine Supplementation in aldh5a1 KO Mice ( aldh5a1 −/− ) , a Phenocopy of the GABA Metabolic Disorder Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD)

Study Objectives SSADHD is an orphan disorder of γ‐aminobutyric acid (GABA) metabolism that manifests a neurobehavioral phenotype with seizures, hyperactivity, anxiety, and attention‐deficit and obsessive‐compulsive disorders (Malaspina, 2016). Autosomal‐recessively inherited mutations in ALDH5A1, the gene encoding SSADH, lead to accumulation of GABA (a major brain inhibitory neurotransmitter) and its metabolite γ‐hydroxybutyrate (GHB). These metabolic abnormalities associate with disruptions of both GABAergic and glutamatergic neurotransmission, documented in both patients and aldh5a1 −/− mice (Buzzi 2006; Wu, 2006; Pearl, 2009; Reis, 2012; Vogel, 2017). Of interest, patients and aldh5a1 −/− mice manifest significantly depleted levels of glutamine ( gln ), a substrate and precursor of both GABA and glutamate in brain astrocytes (Gibson, 2003; Gupta, 2004; Chowdhury, 2007). In this study, we hypothesized that maternal dietary gln supplementation during pregnancy would show efficacy in aldh5a1 −/− mice by improving body weight, lifespan, behavior, and metabolic parameters. Methods Aldh5a1 +/− ( het ) mates were liberally fed either a 4% gln ‐supplemented or an isocaloric and isonitrogenous gln ‐free diet during gestation and the post‐natal period . Aldh5a1 −/− ( mut ) and aldh5a1 +/+ ( wt) offspring were monitored for body weight and seizure activity until post‐natal day 30 (P30), at which time mice were sacrificed and tissues harvested. Open‐field behavioral testing of the offspring was performed at P18–19. To this end, a single mouse was placed in a circular arena with 3 defined zones (center, border, and wall), and allowed to freely explore for 10 minutes. Distance moved, velocity, time spent in each zone, and duration of movement or non‐movement was tracked with the EthoVision XT software (Noldus). Brain and liver gln concentrations were quantified using the EnzyChrom™ Glutamine Assay Kit (BioAssay Systems). Results Gln supplementation significantly enhanced liver and brain gln concentrations in wt offspring but had no significant effect in the same tissues obtained from mut mice (ANOVA‐Liver: p<0.05; Diet , p<0.001; Genotype , p<0.0.007; Diet × Genotype , p<0.001; ANOVA‐Brain: p<0.05; Diet , p<0.001; Genotype , p<0.001; Diet × Genotype , p<0.025). We found no improvement in mut truncated lifespan and impaired body weight. Gln supplementation however, normalized mut open field parameters for distance moved, velocity, and duration of movement or non‐movement in comparison to wt behavior (p<0.05). Conclusion Additional histochemical, metabolic, and gene‐expression analyses are in progress to probe the mechanism(s) underlying the neurobehavioral effect of gln supplementation in SSADHD. We focus in particular on the possibility of an accelerated metabolic turnover of dietary gln after intestinal absorption to account for the lack of increase in tissue gln concentrations in aldh5a1 −/− . However, our findings already suggest that gln supplementation may have therapeutic efficacy in the mitigation of the neuropsychiatric morbidity of the disease. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .