Abstract
The disorders of the glutamatergic neurotransmission have been associated with pathogenesis of autism. In this study we evaluated the impact of the in vivo and ex vivo test methodology on measurements of levels of neurotransmitter amino acids in hippocampus of rats for valproic acid- (VPA) and thalidomide- (THAL) induced models of autism. The main goal was to compare the changes in concentrations of glutamate (Glu), glutamine (Gln) and GABA between both autistic groups and the control, measured in vivo and ex vivo in homogenates. The rat pups underwent three in vivo tests: ultrasonic vocalization (USV), magnetic resonance spectroscopy (MRS) and unilateral microdialysis of the hippocampus. Analyses of homogenates of rat hippocampus were performed using high-performance liquid chromatography (HPLC) and nuclear magnetic resonance (NMR) spectroscopy. For the statistical analysis, we performed univariate and multivariate tests. USV test, which is considered in rodents as an indicator of pathology similar to autism, showed decreased USV in VPA and THAL groups. In vivo MRS studies demonstrated increases of Glu content in male rat’s hippocampus in VPA and THAL groups, while the microdialysis, which allows examination of the contents in the extracellular space, detected decreases in the basal level of Gln concentrations in VPA and THAL groups. Ex vivo HPLC studies showed that levels of Glu, Gln and GABA significantly increased in male rat’s hippocampus in the VPA and THAL groups, while NMR studies showed increased levels of Gln and GABA in the VPA group. Collectively, these results are consistent with the hypothesis suggesting the role of the glutamatergic disturbances on the pathogenesis of autism. For all methods used, the values of measured changes were in the same direction. The orthogonal partial least square discriminant analysis confirmed that both animal models of autism tested here can be used to trace neurochemical changes in the brain.
Highlights
Autism spectrum disorders (ASD) including autism itself, comprise a group of severe neurodevelopmental disabilities that is revealed during the first 3 years of life
The THAL group was the most different from the control group, in which the number of calls decreased in F + M, F and M subgroups to levels of 20 (1–143, percentiles: 26/109/143), 33 (12–109, percentiles: 79/109/109) and 20 (1–143, percentiles: 23/26/143), respectively
We observed Glu concentration increase of 20% in the valproic acid- (VPA) group and 18% in the THAL group
Summary
Autism spectrum disorders (ASD) including autism itself, comprise a group of severe neurodevelopmental disabilities that is revealed during the first 3 years of life. It seems that imbalances between excitation and inhibition contribute to the development and maintenance of ASD (Lee et al, 2017) This assertion is supported by the results of the receptor protein expression studies. Hyperactivity of NMDARs that has been demonstrated in animal models of autism seems to be mediated by mGluR5, probably because of partial reduction caused by mGluR5 antagonists (Carlson, 2012). This provided the basis for the use of NMDAR and mGluR5 antagonists in the experimental treatment of behavioral disorders in ASD patients (Chez et al, 2007; Jacquemont et al, 2011). Important information supporting the glutamate hypothesis of autism come from genetic research, which showed association between autism and genes for kainate and AMPA receptors, as well as for NMDARs, mGluRs or glutamate transporters (Jacob et al, 2011; Carlson, 2012; Yoo et al, 2012)
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