D-aspartate dysregulation in Ddo(-/-) mice modulates phencyclidine-induced gene expression changes of postsynaptic density molecules in cortex and striatum.

Abstract

N-methyl-D-aspartate receptor (NMDAR) hypofunction has been considered a key alteration in schizophrenia pathophysiology. Thus, several strategies aimed at enhancing glutamatergic transmission, included the introduction in therapy of D-amino acids, such as D-serine and D-cycloserine augmentation, have been proposed to counteract difficult-to-treat symptoms or treatment-resistant forms of schizophrenia. Another D-amino acid, D-aspartate, has recently gained increasing interest for its role in NMDAR activation and has been found reduced in post-mortem cortex of schizophrenia patients. NMDAR is the core of the postsynaptic density (PSD), a postsynaptic site involved in glutamate signaling and responsive to antipsychotic treatment. In this study, we investigated striatal and cortical gene expression of key PSD transcripts (i.e. Homer1a, Homer1b/c, and PSD-95) in mice with persistently elevated brain D-aspartate-levels, i.e. the D-aspartate-oxidase knockout mice (Ddo(-/-)). These animal models were analyzed both in naive condition and after phencyclidine (PCP) treatment. Naive Ddo(-/-) mice showed decreased Homer1a expression in the prefrontal cortex, increased Homer1b/c expression in the striatum, and decreased PSD-95 expression in the striatum and in the cortex. Acute PCP treatment restored, and even potentiated, Homer1a expression in the prefrontal cortex of mutant mice, while it had limited effects on the other genes. These results suggest that persistently elevated D-aspartate, by enhancing NMDA transmission, may cause complex adaptive mechanisms affecting Homer1a, which in turn may explain the recently demonstrated protective effects of this D-amino acid against PCP-induced behavioral alterations, such as ataxic behavior.

• Authors: Andrea de Bartolomeis, Francesco Errico, Giuseppe Aceto, Carmine Tomasetti, Alessandro Usiello, Felice Iasevoli
• Journal: Progress in neuro-psychopharmacology & biological psychiatry (Prog Neuropsychopharmacol Biol Psychiatry) Vol. 62 Pg. 35-43 (Oct 01 2015) ISSN: 1878-4216 [Electronic] England
• PMID: 25979765 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Carrier Proteins
• Disks Large Homolog 4 Protein
• Dlg4 protein, mouse
• Homer Scaffolding Proteins
• Membrane Proteins
• Psychotropic Drugs
• RNA, Messenger
• D-Aspartic Acid
• D-Aspartate Oxidase
• Guanylate Kinases
• Phencyclidine

Topics

• Animals
• Ataxia (chemically induced, metabolism)
• Carrier Proteins (metabolism)
• Cerebral Cortex (drug effects, metabolism)
• Corpus Striatum (drug effects, metabolism)
• D-Aspartate Oxidase (genetics, metabolism)
• D-Aspartic Acid (metabolism)
• Disks Large Homolog 4 Protein
• Gene Expression (drug effects)
• Guanylate Kinases (metabolism)
• Homer Scaffolding Proteins
• Membrane Proteins (metabolism)
• Mice, Knockout
• Phencyclidine (pharmacology)
• Psychotropic Drugs (pharmacology)
• RNA, Messenger (metabolism)
• Random Allocation