Pre-frontal parvalbumin interneurons in schizophrenia: a meta-analysis of post-mortem studies

Abstract

Parvalbumin interneurons are fast-spiking GABAergic neurons that provide inhibitory control of cortical and subcortical circuits and are thought to be a key locus of the pathophysiology underlying schizophrenia. In view of the contradictory results regarding the nature of parvalbumin post-mortem findings in schizophrenia, we conducted a quantitative meta-analysis of the data on parvalbumin cell density and parvalbumin mRNA levels in pre-frontal regions in the brains of patients with schizophrenia (n = 274) compared with healthy controls (n = 275). The results suggest that parvalbumin interneurons are reduced in density in the frontal cortex of patients with schizophrenia (Hedges’ g = − 0.27; p = 0.03) and there is a non-significant reduction in parvalbumin mRNA levels (g = − 0.44; p = 0.12). However, certain methodological issues need to be considered in interpreting such results and are discussed in more detail. A meta-regression was conducted for post-mortem interval and year of publication as covariates which were both non-significant, except in the mRNA meta-analysis where post-mortem interval was found to be significant. Overall our findings provide tentative support for the hypothesis that the GABAergic system is deficient in schizophrenia and that parvalbumin-containing interneurons offer a potential target for treatment. However, further well-controlled studies that examine multiple regions and layers are warranted to determine whether parvalbumin alterations are region or layer specific and to test the robustness of the findings further.Electronic supplementary materialThe online version of this article (10.1007/s00702-019-02080-2) contains supplementary material, which is available to authorized users.

The Inflamed Brain in Schizophrenia: The Convergence of Genetic and Environmental Risk Factors That Lead to Uncontrolled Neuroinflammation

“…In addition, ELS is known to have an impact on inhibitory connectivity (Goodwill et al, 2018;Ohta et al, 2020), and previous work suggests that oxidative stress and/or neuroinflammation might underlie the changes in parvalbumin interneurons in response to ELS (Holland et al, 2014;Brenhouse et al, 2019). There is evidence for parvalbumin interneuron dysfunction in SCZ, as they have altered density in the frontal cortex of individuals with SCZ (Kaar et al, 2019). Interestingly, the meninges modulate cortical interneuron migration during development (Borrell and Marín, 2006); future work could interrogate whether changes in meningeal signaling, such as immune molecule signaling, could contribute to alterations in interneuron migration in SCZ.…”

Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: a translational imaging study with ketamine

“…Both the PLc and vSub regions were targeted concurrently for the following reasons. In schizophrenia there are deficits in PV interneuron markers in both the prefrontal cortex and in the hippocampus [16,[22][23][24][25]. In addition, acute and chronic ketamine administration is associated with deficits in PV interneuron markers in both regions [16,17,[26][27][28][29].…”

“…However, it remains possible that ketamine has actions on other neuronal populations that contribute to its effects on striatal dopamine synthesis capacity. Given the evidence of lower PV levels in the frontal cortex and hippocampus in schizophrenia [22][23][24][25] and that acute and chronic ketamine administration leads to lower PV levels in the frontal cortex and hippocampus [16,17,[26][27][28][29], we targeted both regions in our chemogenetics experiment. However, a limitation of targeting both regions is that we are not able to distinguish the relative contribution of each region to the effects we observe.…”

“…[7,98] and see review [6]), and suggested that this is linked to the development of psychosis [99,100] and changes in cortical glutamate levels [101]. Moreover, cortical and hippocampal PV interneuron density and PV protein levels have been shown to be reduced in schizophrenia (see meta-analysis [25] and [102]). Ketamine induces psychotic symptoms in healthy volunteers, and worsens symptoms in patients with schizophrenia [14,15].…”

Mesenchymal stem cells derived extracellular vesicles improve behavioral and biochemical deficits in a phencyclidine model of schizophrenia

“…One possibility suggests that hypofunction at GABAergic interneurons plays an important role 67 . This theory is based on various studies which have proposed that since GABAergic interneurons provide inhibitory control of cortical and subcortical circuits 68,69 , they may lead to glutamatergic and dopaminergic dysfunction, which in turn leads to the symptoms of schizophrenia 70,71 . Moreover, a subset of GABAergic interneurons which express parvalbumin (PV), were shown to be consistently decreased in the PFC of schizophrenic patients 72 .…”