Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia

Abstract

Parvalbumin inhibitory interneurons (PVIs) are crucial for maintaining proper excitatory/inhibitory balance and high-frequency neuronal synchronization. Their activity supports critical developmental trajectories, sensory and cognitive processing, and social behavior. Despite heterogeneity in the etiology across schizophrenia and autism spectrum disorder, PVI circuits are altered in these psychiatric disorders. Identifying mechanism(s) underlying PVI deficits is essential to establish treatments targeting in particular cognition. On the basis of published and new data, we propose oxidative stress as a common pathological mechanism leading to PVI impairment in schizophrenia and some forms of autism. A series of animal models carrying genetic and/or environmental risks relevant to diverse etiological aspects of these disorders show PVI deficits to be all accompanied by oxidative stress in the anterior cingulate cortex. Specifically, oxidative stress is negatively correlated with the integrity of PVIs and the extracellular perineuronal net enwrapping these interneurons. Oxidative stress may result from dysregulation of systems typically affected in schizophrenia, including glutamatergic, dopaminergic, immune and antioxidant signaling. As convergent end point, redox dysregulation has successfully been targeted to protect PVIs with antioxidants/redox regulators across several animal models. This opens up new perspectives for the use of antioxidant treatments to be applied to at-risk individuals, in close temporal proximity to environmental impacts known to induce oxidative stress.

Figure 1

Relationship between oxidative stress and PVI integrity in the ACC of 2–3 month-old animal models relevant to schizophrenia, autism and/or redox dysregulation. (a) Oxidative stress (assessed by the immunoreactivity intensity against 8-oxo-2'-deoxyguanosine (8-oxo-dG), a marker of mitochondrial DNA oxidation), number of PV-IR cells (PV cells) and number of PV cells enwrapped with a WFA-labeled PNN. # indicates models for which the presented data are already published elsewhere.^, The references indexed below provide detailed descriptions of each investigated model and its control. 22q11: mice with a 22q11.2 deletion (LgDel/+) (n=7 animals per group); 15q13.3: mice with a 15q13.3 deletion (Df[h15q13]/+) (n=5, 7); 1q21: mice with a 1q21 deletion (Df[h1q21]/+) (from M Didriksen) (n=4 per group), SRR: serine racemace KO mice (n=5, 7); FMR1: FMR1 KO mice (n=7, 8); PV-GCLC: mice with conditional KO of GCLC (catalytic subunit of the key synthesizing enzyme of GSH) in PVIs (n=5 per group); GRIN2A: GRIN2A KO mice (n=7 per group); GCLM: GCLM KO mice (n=5 per group); GCLM GBR: GCLM KO mice treated with dopamine uptake inhibitor GBR12909 during postnatal development (P10-20) (n=5 per group); GRIN2A GBR: GRIN2A KO mice treated with GBR12909 during postnatal development (P10-20) (n=7 per group); ODS BSO: ODS rats treated with the specific inhibitor of GSH synthesis (BSO) during postnatal development (P5-16) (n=4 per group); NVHL: rats with a neonatal ventral hippocampal lesion (n=6, 7); MAM: rats treated on gestation day GD17 with MAM (n=4, 6); Poly(I:C): mice with a sub-threshold prenatal immune challenge (on GD9) with poly(I:C); +Str: poly(I:C)-treated mice stressed at preadolescence (P30-40) (n=5 per group). Data are depicted by the mean±s.d. (in red: animal models; in blue: their respective controls). *** P<0.001; ** P<0.01, * P<05. (b) Quantile density contours with linear regression (red) and smoothing spline (green) plots illustrating the relationships between changes in oxidative stress (8-oxo-dG-IR), in number of PV cells, and in number of PV cells with WFA-labeled PNN (PV cells+PNN) for all animal models relative to their respective controls (JMP11, SAS Institute, Cary, NC, USA). (c) As in (b) but illustrating the relationship between changes in number of PV cells+PNN and in number of PV cells for all animal models relative to their respective controls. Brief method description: perfused fixed brains from all animal models were sent to Lausanne where immunohistological preparation, image acquisition and analyses were performed blindly using the methods described previously. Three to four sections per animal were used for the analyses. Analyses of 8-oxo-dG-IR intensity, numbers of PV-IR cells and PV-IR cells surrounded with a WFA-labeled PNN were done in a region of interest comprising all layers of the ACC. Oxidative stress was assessed in all cells of ROI. Each animal model was compared with its own control animals. Only males were analyzed, except for the GRIN2A model where individuals from both sexes were used. On the basis of previously analyzed data, sample size was choosen to detect ~25% change in number of PV-IR cells and ~75% change in 8-oxo-dG intensity with a power of 80% at a significant α-value set to P=0.05. Statistical significance was tested by comparing means of the different models with their respective controls using the Dunnett’s test. When variances were not equal, we used the Welch’s test to give confidence and confirm the Dunnett’s test outcome. ACC, anterior cingulate cortex; BSO, buthionine sulphoximine; KO, knockout; MAM, methylazoxymethanol acetate; NVHL, neonatal ventral hippocampal lesion; ODS, osteogenic disorder Shionogi; PNN, perineuronal net; PV, parvalbumin; PV-IR, parvalbumin-immunoreactive; PVI, parvalbumin inhibitory interneuron; WFA, Wisteria floribunda agglutinin.

Figure 2

A common mechanism of oxidative stress-induced PVI/PNN deficit in animals modeling genetic and/or environmental risks, and experimental disruptions of brain development relevant to schizophrenia and/or autism. Bold boxes and text represent animal models where PVI deficit has been linked to redox dysregulation/oxidative stress in the present study or in published works: 22q11: mice with a 22q11.2 deletion (LgDel/+); 15q13.3: mice with a 15q13.3 deletion (Df[h15q13]/+); 1q21: mice with a 1q21 deletion (Df[h1q21]/+), SRR: serine racemace KO mice; FMR1: FMR1 KO mice; PV-GCLC: mice with conditional KO of GCLC in PVIs; GRIN2A: GRIN2A KO mice; GCLM: GCLM KO mice; GCLM+hyperdopaminergia: GCLM KO mice treated with dopamine uptake inhibitor GBR12909 during postnatal development (P10-20); GRIN2A+hyperdopaminergia: GRIN2A KO mice treated with GBR12909 during postnatal development (P10-20); ODS+transient GSH deficit: osteogenic disorder Shionogi rats treated with the specific inhibitor of GSH synthesis (buthionine sulphoximine) during postnatal development (P5-16); NVHL: rats with a neonatal ventral hippocampal lesion; MAM: rats treated prenatally (GD17) with methylazoxymethanol acetate; Poly(I:C)+stress: mice with a sub-threshold prenatal immune challenge (on GD9) with poly(I:C) followed by chronic stress at preadolescence (P30-40); GRIN1+social isolation: isolated mice with conditional GRIN1 KO in forebrain interneurons; rats socially isolated; social defeated rats; ketamine administration; DISC1 mutant mice; and^, selenoprotein P (SEPP1) KO mice). Boxes with normal text represent animal models for which PVI deficit is very likely linked to redox dysregulation/oxidative stress. Indeed, PVI deficit and oxidative stress are reported in separate studies for the following models: prenatal stress;^, maternal separation in rats;^, early-life iron deficiency;^, hypoxia;^, DTNB1 mutant mice; and^, PCP.^, Mice with COX10 KO in PVIs (PV-COX10) and PGC1-α KO mice^, are models of mitochondria impairment which likely display redox dysregulation/oxidative stress. Dotted boxes, animal models with PVI deficit for which redox dysregulation/oxidative stress may be expected based on literature data: CHRNA7 KO mice;^, mice with disrupted NRG1/ErbB4 signaling. KO, knockout; NVHL, neonatal ventral hippocampal lesion; PCP, postnatal treatment with phencyclidine; PNN, perineuronal net; PV, parvalbumin; PV-IR, parvalbumin-immunoreactive; PVI, parvalbumin inhibitory interneuron.^{, ,}