Synaptic loss in schizophrenia: a meta-analysis and systematic review of synaptic protein and mRNA measures

Abstract

Although synaptic loss is thought to be core to the pathophysiology of schizophrenia, the nature, consistency and magnitude of synaptic protein and mRNA changes has not been systematically appraised. Our objective was thus to systematically review and meta-analyse findings. The entire PubMed database was searched for studies from inception date to the 1st of July 2017. We selected case-control postmortem studies in schizophrenia quantifying synaptic protein or mRNA levels in brain tissue. The difference in protein and mRNA levels between cases and controls was extracted and meta-analysis conducted. Among the results, we found a significant reduction in synaptophysin in schizophrenia in the hippocampus (effect size: -0.65, p<0.01), frontal (effect size: -0.36, p=0.04), and cingulate cortices (effect size: -0.54, p=0.02), but no significant changes for synaptophysin in occipital and temporal cortices, and no changes for SNAP-25, PSD-95, VAMP and syntaxin in frontal cortex. There were insufficient studies for meta-analysis of complexins, synapsins, rab3A and synaptotagmin and mRNA measures. Findings are summarised for these, which generally show reductions in SNAP-25, PSD-95, synapsin and rab3A protein levels in the hippocampus but inconsistency in other regions. Our findings of moderate-large reductions in synaptophysin in hippocampus and frontal cortical regions, and a tendency for reductions in other pre- and post-synaptic proteins in the hippocampus are consistent with models that implicate synaptic loss in schizophrenia. However, they also identify potential differences between regions and proteins, suggesting synaptic loss is not uniform in nature or extent.

Contrasting effects of chronic lithium, haloperidol and olanzapine exposure on synaptic clusters in the rat prefrontal cortex

“…Neuroimaging and post-mortem studies of individuals with SCZ or BD show reduced brain volume and spine density, particularly in the prefrontal and anterior cingulate cortex and hippocampus relative to healthy controls [1][2][3][4] . These changes coincide with reduced protein and/or mRNA levels of various synaptic markers [5][6][7][8][9][10][11] . Whereas the majority of these data were derived from post-mortem human material, the recent development of the UCB-J PET tracers, which specifically interact with the presynaptic Synaptic Vesicle glycoprotein 2A (SV2A), has enabled visualisation of pre-synaptic terminal density in the living human brain [12][13][14] .…”

“…Our data presented here provide evidence that APDs are unlikely to account for the reduced SV2A binding in SCZ patients as observed by PET 19 . More broadly, the lack of change in either SV2A, NLGN or synaptic (overlapping SV2A/NLGN) cluster density suggests APD treatment may be unrelated to changes in other synaptic markers found in human post mortem SCZ tissue, such as reduced SYN levels 8,64 . Whether SV2A protein levels are reduced in BD and SCZ post-mortem brain tissue has yet to be investigated, but could be expected to reflect the same changes as those observed with SYN.…”

A within‐subject consideration of the psychotic spectrum disorder concept in a patient in remission associated with cortical gray matter recovery

“…Additional evidence for the DMN and remission has been reported by Manoliou and colleagues . Loss of key synaptic proteins that are essential for spine formation and plasticity in cortical and hippocampal areas, including the subthalamic nucleus, is likely to be critical for the pathophysiology of schizophrenia and response to APD treatment …”

“…31 Loss of key synaptic proteins that are essential for spine formation and plasticity in cortical and hippocampal areas, including the subthalamic nucleus, is likely to be critical for the pathophysiology of schizophrenia and response to APD treatment. 15,32 There was nothing remarkable about the baseline brain MRI in this patient, including total gray matter compared with other patients in the study, or specific regional shapes or sizes, to suggest some comparable improvement in gray matter as the basis for the remission of the bipolar and psychotic depressive periods previously noted. Conceivably, gray matter renewal in other regions of the brain may have been responsible for the termination of those periods.…”

scGRNom: a computational pipeline of integrative multi-omics analyses for predicting cell-type disease genes and regulatory networks

“…From an oligodendrocyte-based context, we observed that multiple forms of synapse function and regulation were enriched -specifically, the regulation of trans-synaptic signaling (p<1.95e-8) [45], modulation of chemical synaptic transmission (p<1.80e-8) [46], and neuron-to-neuron synapses (p<2.57e-11) [47]. The overarching theme of these observations concerns furthered impacts on signaling and transmission between neurons which Schizophrenia pathology widely believes to be implicated [45,46,48,49]. This is in line with the physical effects of SCZ, both positive and negative, as overactive dopamine channels have been suggested to create hallucinations (visual and auditory) [50], which is a hallmark feature of SCZ diagnoses.…”