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Glutamatergic dysfunction is implicated in schizophrenia pathoaetiology, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls (log coefficient of variation ratio: CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data (Hartigan’s unimodality dip test). MEDLINE and EMBASE databases were searched from inception to September 2022 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia. 123 studies reporting on 8256 patients and 7532 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: CVR = 0.15,p p = 0.003; Glx: CVR = 0.11,p = 0.002), dorsolateral prefrontal cortex (glutamine: CVR = 0.14,p = 0.05; Glx: CVR = 0.25,p p = 0.008; Glx: CVR = 0.19,p = 0.008). Studies in younger, more symptomatic patients were associated with greater variability in the basal ganglia (BG glutamate with age:z = −0.03,p = 0.003, symptoms:z = 0.007,p = 0.02) and temporal lobe (glutamate with age:z = −0.03,p = 0.02), while studies with older, more symptomatic patients associated with greater variability in MFC (glutamate with age:z = 0.01,p = 0.02, glutamine with symptoms:z = 0.01,p = 0.02). For individual patient data, most studies showed a unimodal distribution of glutamatergic metabolites. Meta-analysis of mean differences found lower MFC glutamate (g = −0.15,p = 0.03), higher thalamic glutamine (g = 0.53,p g = 0.28,p z = −0.02,p z = −0.03,p = 0.02) in patients relative to controls. Patient PANSS total score was positively associated with glutamate SMD in BG (z = 0.01,p = 0.01) and temporal lobe (z = 0.05,p = 0.008). Further research into the mechanisms underlying greater glutamatergic metabolite variability in schizophrenia and their clinical consequences may inform the identification of patient subgroups for future treatment strategies.

The in situ hybridization Allen Mouse Brain Atlas was mined for proteases expressed in the somatosensory cerebral cortex. Among the 480 genes coding for protease/peptidases, only four were found enriched in cortical interneurons: Reln coding for reelin; Adamts8 and Adamts15 belonging to the class of metzincin proteases involved in reshaping the perineuronal net (PNN) and Mme encoding for Neprilysin, the enzyme degrading amyloid β-peptides. The pattern of expression of metalloproteases (MPs) was analyzed by single-cell reverse transcriptase multiplex PCR after patch clamp and was compared with the expression of 10 canonical interneurons markers and 12 additional genes from the Allen Atlas. Clustering of these genes by K-means algorithm displays five distinct clusters. Among these five clusters, two fast-spiking interneuron clusters expressing the calcium-binding protein Pvalb were identified, one co-expressing Pvalb with Sst (PV-Sst) and another co-expressing Pvalb with three metallopeptidases Adamts8, Adamts15 and Mme (PV-MP). By using Wisteria floribunda agglutinin, a specific marker for PNN, PV-MP interneurons were found surrounded by PNN, whereas the ones expressing Sst, PV-Sst, were not.

Background: Schneiderian first rank symptoms (FRS) are characterized by a diminished demarcation of self-other boundaries, causing misattribution of self-generated thoughts and actions to external sources. We have shown that introducing sensorimotor prediction error (SPE) by a robotic device in healthy subjects can induce a Feeling of a Presence (FoP) which is related to the FRS (Blanke et al. 2014). Here, we tested if SPE may induce auditory misattribution in psychotic patients and if this is related to neural connectivity in the temporoparietal cortex, insular cortex and fronto-parietal cortex (FoP Network). Methods: Participants manipulated a haptic robotic system inducing a sensorimotor conflict while performing a self-other auditory discrimination task. 31 early psychotic patients (19 with and 12 without FRS) and 20 controls participated in the experiment. We measured accuracy (d′) on auditory self-other discrimination task during sensorimotor conflict induction or control condition, functional connectivity magnitude in a priori FoP network, and calculated correlation between the two measures. Results: Patients with FRS had reduced accuracy in auditory self-other discrimination when sensorimotor conflict was induced (F(2, 44)=6.68, p=.002). rsfMRI connectivity analysis indicated lower connectivity for these patients in regions of the FoP network compared to the non-first rank and control groups (p=.015, p=.014). The level of functional connectivity in the FoP network correlated with the reduction of self-other discrimination in the FRS+ group (r=-0.56, p=.03). Conclusions: Experimental induction of SPE can cause self-other confusion in the auditory domain. This deficit in self-other discrimination was correlated to specifically reduced connectivity in the FoP network related to sensorimotor self-representation.