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.

Dysfunctional D-aspartate metabolism in BTBR mouse model of idiopathic autism

Pasqualetti M.;Usiello A.
2020-01-01

Abstract

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.
2020
Nuzzo, T.; Sekine, M.; Punzo, D.; Miroballo, M.; Katane, M.; Saitoh, Y.; Galbusera, A.; Pasqualetti, M.; Errico, F.; Gozzi, A.; Mothet, J. -P.; Homma, H.; Usiello, A.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/1060416
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