Neurotransmitter alterations in embryonic succinate semialdehyde dehydrogenase (SSADH) deficiency suggest a heightened excitatory state during development

Embryos were obtained from pregnant dams sacrificed at E (embryo day of life) 10–13, 14–15, 16–17, 18–19 and newborn mice. Intact embryos were extracted and metabolites quantified by isotope dilution mass spectrometry (n = 5–15 subjects, Aldh5a1+/+ and Aldh5a1-/-) for each gestational age group. Data was evaluated using the t test and one-way ANOVA with Tukey post hoc analysis. Significance was set at the 95th centile.GABA and DHHA were significantly elevated at all gestational ages in Aldh5a1-/- mice, while GB was increased only late in gestation; SSA was not elevated at any time point. GHB and D-2-HG increased in an approximately linear fashion with gestational age. Correlative studies in human amniotic fluid from SSADH-deficient pregnancies (n = 5) also revealed significantly increased GABA.Our findings indicate early GABAergic alterations in Aldh5a1-/- mice, possibly exacerbated by other metabolites, which likely induce a heightened excitatory state that may predispose neural networks to epilepsy in these animals.Succinic semialdehyde dehydrogenase (SSADH) deficiency (aldehyde dehydrogenase 5a1 (Aldh5a1); E.C. 1.2.1.24; OMIM 271980, 610045) is a rare neurometabolic defect of the GABA catabolic pathway (Fig. 1). The phenotype is variably that of a static encephalopathy, associated with developmental delays, hypotonia, ataxia, defects or absence of speech, and seizures [1]. Older patients may demonstrate a prominent component of neuropsychiatric morbidity. A cardinal finding from imaging of patients is hyper-intense signals in the globi pallidi bilaterally [2]. Identification of affected probands is facilitated by detection of increased γ-hydroxybutyric acid (GHB) during routine urine organic acid analysis. GHB, a by-product of defective GABA catabolism (Fig. 1), is a compound with its own unique pharmacological profile, and it remains a topic of debate as to whether it is a neurotransmitter as is the case for its parent compound, GABA [3]. Treatment options for p