TY - JOUR
T1 - Dysfunctional D-aspartate metabolism in BTBR mouse model of idiopathic autism
AU - Nuzzo, Tommaso
AU - Sekine, Masae
AU - Punzo, Daniela
AU - Miroballo, Mattia
AU - Katane, Masumi
AU - Saitoh, Yasuaki
AU - Galbusera, Alberto
AU - Pasqualetti, Massimo
AU - Errico, Francesco
AU - Gozzi, Alessandro
AU - Mothet, Jean Pierre
AU - Homma, Hiroshi
AU - Usiello, Alessandro
PY - 2020/12
Y1 - 2020/12
N2 - Background: Autism spectrum disorders (ASD) comprise a heterogeneous group of neurodevelopmental conditions characterized by impairment in social interaction, deviance in communication, and repetitive behaviors. Dysfunctional ionotropic NMDA and AMPA receptors, and metabotropic glutamate receptor 5 activity at excitatory synapses has been recently linked to multiple forms of ASD. Despite emerging evidence showing that D-aspartate and D-serine are important neuromodulators of glutamatergic transmission, no systematic investigation on the occurrence of these D-amino acids in preclinical ASD models has been carried out. Methods: Through HPLC and qPCR analyses we investigated D-aspartate and D-serine metabolism in the brain and serum of four ASD mouse models. These include BTBR mice, an idiopathic model of ASD, and Cntnap2−/−, Shank3−/−, and 16p11.2+/− mice, three established genetic mouse lines recapitulating high confidence ASD-associated mutations. Results: Biochemical and gene expression mapping in Cntnap2−/−, Shank3−/−, and 16p11.2+/− failed to find gross cerebral and serum alterations in D-aspartate and D-serine metabolism. Conversely, we found a striking and stereoselective increased D-aspartate content in the prefrontal cortex, hippocampus and serum of inbred BTBR mice. Consistent with biochemical assessments, in the same brain areas we also found a robust reduction in mRNA levels of D-aspartate oxidase, encoding the enzyme responsible for D-aspartate catabolism. Conclusions: Our results demonstrated the presence of disrupted D-aspartate metabolism in a widely used animal model of idiopathic ASD. General significance: Overall, this work calls for a deeper investigation of D-amino acids in the etiopathology of ASD and related developmental disorders.
AB - Background: Autism spectrum disorders (ASD) comprise a heterogeneous group of neurodevelopmental conditions characterized by impairment in social interaction, deviance in communication, and repetitive behaviors. Dysfunctional ionotropic NMDA and AMPA receptors, and metabotropic glutamate receptor 5 activity at excitatory synapses has been recently linked to multiple forms of ASD. Despite emerging evidence showing that D-aspartate and D-serine are important neuromodulators of glutamatergic transmission, no systematic investigation on the occurrence of these D-amino acids in preclinical ASD models has been carried out. Methods: Through HPLC and qPCR analyses we investigated D-aspartate and D-serine metabolism in the brain and serum of four ASD mouse models. These include BTBR mice, an idiopathic model of ASD, and Cntnap2−/−, Shank3−/−, and 16p11.2+/− mice, three established genetic mouse lines recapitulating high confidence ASD-associated mutations. Results: Biochemical and gene expression mapping in Cntnap2−/−, Shank3−/−, and 16p11.2+/− failed to find gross cerebral and serum alterations in D-aspartate and D-serine metabolism. Conversely, we found a striking and stereoselective increased D-aspartate content in the prefrontal cortex, hippocampus and serum of inbred BTBR mice. Consistent with biochemical assessments, in the same brain areas we also found a robust reduction in mRNA levels of D-aspartate oxidase, encoding the enzyme responsible for D-aspartate catabolism. Conclusions: Our results demonstrated the presence of disrupted D-aspartate metabolism in a widely used animal model of idiopathic ASD. General significance: Overall, this work calls for a deeper investigation of D-amino acids in the etiopathology of ASD and related developmental disorders.
KW - Autism spectrum disorder
KW - D-aspartate
KW - D-aspartate oxidase
KW - D-serine
KW - NMDA receptors
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U2 - 10.1016/j.bbapap.2020.140531
DO - 10.1016/j.bbapap.2020.140531
M3 - Article
C2 - 32853769
AN - SCOPUS:85090165174
VL - 1868
JO - Biochimica et Biophysica Acta - Proteins and Proteomics
JF - Biochimica et Biophysica Acta - Proteins and Proteomics
SN - 1570-9639
IS - 12
M1 - 140531
ER -