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.