NMDA glutamate receptor antagonist MK ‐801 induces proteome changes in adult human brain slices which are partially counteracted by haloperidol and clozapine

Schizophrenia presents a complex molecular pathophysiology, and the hypofunction of the glutamatergic NMDA receptor is recognized as one of the primary mechanisms. Using adult human brain-derived slice cultures and proteomics, we have identified altered pathways in NMDA antagonist MK-801-treated slices, some of which are associated with schizophrenia in previous works. By co-treating the slices with MK-801 and antipsychotics, we showed that clozapine was more effective in attenuating the molecular alterations caused by NMDAr hypofunction than haloperidol. AbstractDeciphering the molecular pathways associated with N-methyl-D-aspartate receptor (NMDAr) hypofunction and its interaction with antipsychotics is necessary to advance our understanding of the basis of schizophrenia, as well as our capacity to treat this disease. In this regard, the development of human brain-derived models that are amenable to studying the neurobiology of schizophrenia may contribute to filling the gaps left by the widely employed animal models. Here, we assessed the proteomic changes induced by the NMDA glutamate receptor antagonist MK-801 on human brain slice cultures obtained from adult donors submitted to resective neurosurgery. Initially, we demonstrated that MK-801 diminishes NMDA glutamate receptor signaling in human brain slices in culture. Next, using mass-spectrometry-based proteomics and systems biology in silico analyses, we found that MK-801 led to alterations in proteins related to sever...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: ORIGINAL ARTICLE Source Type: research