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

Author(s)

de Almeida, Valeria ; Mendes, Niele Dias ; Zuccoli, Giuliana S. ; Reis-de-Oliveira, Guilherme ; Almeida, Glaucia M. ; Podolsky-Gondim, Guilherme Gozzoli ; Neder, Luciano ; Martins-de-Souza, Daniel ; Sebollela, Adriano

• Document type: Journal article
• Source: Journal of Neurochemistry; v. 168, n. 3, p. 13-pg., 2024-02-08.

Abstract

Deciphering 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 several pathways previously associated with schizophrenia pathophysiology, including ephrin, opioid, melatonin, sirtuin signaling, interleukin 8, endocannabinoid, and synaptic vesicle cycle. We also evaluated the impact of both typical and atypical antipsychotics on MK-801-induced proteome changes. Interestingly, the atypical antipsychotic clozapine showed a more significant capacity to counteract the protein alterations induced by NMDAr hypofunction than haloperidol. Finally, using our dataset, we identified potential modulators of the MK-801-induced proteome changes, which may be considered promising targets to treat NMDAr hypofunction in schizophrenia. This dataset is publicly available and may be helpful in further studies aimed at evaluating the effects of MK-801 and antipsychotics in the human brain. (AU)

• FAPESP's process: 21/12263-2 - Tissue-molecular alterations associated with viral infections in adult human brain slice cultures
• Grantee: Glaucia Maria de Almeida
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/18242-1 - Biochemical pathways affected by cannabinoid drugs of human oligodendrocytes
• Grantee: Valéria de Almeida
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 18/06614-4 - Determination of neuronal function and oxidative metabolic profile in free-floating adult human brain-derived slice cultures
• Grantee: Glaucia Maria de Almeida
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 17/25588-1 - From the basic understanding to clinical biomarkers to schizophrenia: a neuroproteomics-centered multidisciplinary study
• Grantee: Daniel Martins-de-Souza
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 14/25681-3 - Molecular basis of the toxicity of protein oligomers associated to brain amyloidosis
• Grantee: Adriano Silva Sebollela
• Support Opportunities: Research Grants - Young Investigators Grants