Aller au contenuAller au menuAller à la recherche

Joseph Coyle "NMDA Receptor Hypofunction and the Pathophysiology of Schizophrenia"

Abstract :

Schizophrenia is characterized by positive symptoms (delusions, hallucinations), negative symptoms (anhedonia, poverty of thought, asociality) and cognitive deficits. NMDA receptor antagonists (PCP, ketamine) best replicate these symptoms in studies with normal volunteers. Post-mortem studies have revealed elevated NMDA receptor negative modulators in schizophrenia. Recent genetics studies have implicated several risk genes that affect NMDA receptor function including G72, D-amino acid oxidase and NR2B. Agents that enhance NMDA receptor function including D-cycloserine, glycine and D-serine have been shown to reduce negative symptoms and variably to improve cognition in patients receiving concurrent antipsychotic drugs. Electrophysiologic studies indicated that NMDA receptors on the fast-firing parvalbumen positive GABAergic interneurons are most sensitive NMDA receptor antagonists such as ketamine. Subchronic ketamine down-regulates cortical GAD67, parvalbbumen and the GABA transporter, changes identical to those observed in schizophrenia in post-mortem studies. To re-create NMDA receptor hypofunction in mice, the gene for serine racemase (SR), which synthesizes D-serine, was inactivated. SR-/- mice exhibit a behavioral endophenotype consistent with schizophrenia, impaired NMDA receptor function and reduce long-term potentiation. Furthermore, SR-/- mice have less dendritic complexity and reduced spine number on pyramidal neurons in the frontal and sensory cortices. These results provide compelling evidence of a “pathologic circuit” in schizophrenia where the primary pathology is cortical and psychosis is a downstream event. This circuit provides novel targets for drugs that could treat the core features of schizophrenia.

Selected publications

Unintended changes in cognition, mood, and behavior arising from cell-based interventions for neurological conditions: ethical challenges.Duggan PS, Siegel AW, Blass DM, Bok H, Coyle JT,et al Am J Bioeth. 2009 May;9(5):31-6.    
MicroRNAs suggest a new mechanism for altered brain gene expression in schizophrenia.Coyle JT.Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):2975-6. Epub 2009 Feb 26. No abstract available.