Machine Learning algorithm unveils glutamatergic alterations in the post-mortem schizophrenia brain.
Journal
Schizophrenia (Heidelberg, Germany)
ISSN: 2754-6993
Titre abrégé: Schizophrenia (Heidelb)
Pays: Germany
ID NLM: 9918367987006676
Informations de publication
Date de publication:
25 02 2022
25 02 2022
Historique:
received:
05
07
2021
accepted:
06
12
2021
entrez:
26
2
2022
pubmed:
27
2
2022
medline:
27
2
2022
Statut:
epublish
Résumé
Schizophrenia is a disorder of synaptic plasticity and aberrant connectivity in which a major dysfunction in glutamate synapse has been suggested. However, a multi-level approach tackling diverse clusters of interacting molecules of the glutamate signaling in schizophrenia is still lacking. We investigated in the post-mortem dorsolateral prefrontal cortex (DLPFC) and hippocampus of schizophrenia patients and non-psychiatric controls, the levels of neuroactive D- and L-amino acids (L-glutamate, D-serine, glycine, L-aspartate, D-aspartate) by HPLC. Moreover, by quantitative RT-PCR and western blotting we analyzed, respectively, the mRNA and protein levels of pre- and post-synaptic key molecules involved in the glutamatergic synapse functioning, including glutamate receptors (NMDA, AMPA, metabotropic), their interacting scaffolding proteins (PSD-95, Homer1b/c), plasma membrane and vesicular glutamate transporters (EAAT1, EAAT2, VGluT1, VGluT2), enzymes involved either in glutamate-dependent GABA neurotransmitter synthesis (GAD65 and 67), or in post-synaptic NMDA receptor-mediated signaling (CAMKIIα) and the pre-synaptic marker Synapsin-1. Univariable analyses revealed that none of the investigated molecules was differently represented in the post-mortem DLPFC and hippocampus of schizophrenia patients, compared with controls. Nonetheless, multivariable hypothesis-driven analyses revealed that the presence of schizophrenia was significantly affected by variations in neuroactive amino acid levels and glutamate-related synaptic elements. Furthermore, a Machine Learning hypothesis-free unveiled other discriminative clusters of molecules, one in the DLPFC and another in the hippocampus. Overall, while confirming a key role of glutamatergic synapse in the molecular pathophysiology of schizophrenia, we reported molecular signatures encompassing elements of the glutamate synapse able to discriminate patients with schizophrenia and normal individuals.
Identifiants
pubmed: 35217646
doi: 10.1038/s41537-022-00231-1
pii: 10.1038/s41537-022-00231-1
pmc: PMC8881508
doi:
Types de publication
Journal Article
Langues
eng
Pagination
8Subventions
Organisme : NCI NIH HHS
ID : F32 CA090073
Pays : United States
Organisme : Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)
ID : 2017M42834
Informations de copyright
© 2022. The Author(s).
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