Advertisement

Early-Life Insults Impair Parvalbumin Interneurons via Oxidative Stress: Reversal by N-Acetylcysteine

Published:November 08, 2012DOI:https://doi.org/10.1016/j.biopsych.2012.09.020

      Background

      A hallmark of the pathophysiology of schizophrenia is a dysfunction of parvalbumin-expressing fast-spiking interneurons, which are essential for the coordination of neuronal synchrony during sensory and cognitive processing. Oxidative stress as observed in schizophrenia affects parvalbumin interneurons. However, it is unknown whether the deleterious effect of oxidative stress is particularly prevalent during specific developmental time windows.

      Methods

      We used mice with impaired synthesis of glutathione (Gclm knockout [KO] mice) to investigate the effect of redox dysregulation and additional insults applied at various periods of postnatal development on maturation and long-term integrity of parvalbumin interneurons in the anterior cingulate cortex.

      Results

      A redox dysregulation, as in Gclm KO mice, renders parvalbumin interneurons but not calbindin or calretinin interneurons vulnerable and prone to exhibit oxidative stress. A glutathione deficit delays maturation of parvalbumin interneurons, including their perineuronal net. Moreover, an additional oxidative challenge in preweaning or pubertal but not in young adult Gclm KO mice reduces the number of parvalbumin-immunoreactive interneurons. This effect persists into adulthood and can be prevented with the antioxidant N-acetylcysteine.

      Conclusions

      In Gclm KO mice, early-life insults inducing oxidative stress are detrimental to immature parvalbumin interneurons and have long-term consequences. In analogy, individuals carrying genetic risks to redox dysregulation would be potentially vulnerable to early-life environmental insults, during the maturation of parvalbumin interneurons. Our data support the need to develop novel therapeutic approaches based on antioxidant and redox regulator compounds such as N-acetylcysteine, which could be used preventively in young at-risk subjects.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Do K.Q.
        • Cabungcal J.H.
        • Frank A.
        • Steullet P.
        • Cuenod M.
        Redox dysregulation, neurodevelopment, and schizophrenia.
        Curr Opin Neurobiol. 2009; 19: 220-230
        • Yao J.K.
        • Keshavan M.S.
        Antioxidants, redox signaling, and pathophysiology in schizophrenia: An integrative view.
        Antioxid Redox Signal. 2011; 15: 2011-2035
        • Berk M.
        • Copolov D.
        • Dean O.
        • Lu K.
        • Jeavons S.
        • Schapkaitz I.
        • et al.
        N-acetyl cysteine as a glutathione precursor for schizophrenia—a double-blind, randomized, placebo-controlled trial.
        Biol Psychiatry. 2008; 64: 361-368
        • Carmeli C.
        • Knyazeva M.G.
        • Cuenod M.
        • Do K.Q.
        Glutathione precursor N-acetyl-cysteine modulates EEG synchronization in schizophrenia patients: A double-blind, randomized, placebo-controlled trial.
        PLoS One. 2012; 7: e29341
        • Lavoie S.
        • Murray M.M.
        • Deppen P.
        • Knyazeva M.G.
        • Berk M.
        • Boulat O.
        • et al.
        Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in schizophrenia patients.
        Neuropsychopharmacology. 2008; 33: 2187-2199
        • Gysin R.
        • Kraftsik R.
        • Sandell J.
        • Bovet P.
        • Chappuis C.
        • Conus P.
        • et al.
        Impaired glutathione synthesis in schizophrenia: Convergent genetic and functional evidence.
        Proc Natl Acad Sci U S A. 2007; 104: 16621-16626
        • Gokhale A.
        • Larimore J.
        • Werner E.
        • So L.
        • Moreno-De-Luca A.
        • Lese-Martin C.
        • et al.
        Quantitative proteomic and genetic analyses of the schizophrenia susceptibility factor dysbindin identify novel roles of the biogenesis of lysosome-related organelles complex 1.
        J Neurosci. 2012; 32: 3697-3711
        • Goldshmit Y.
        • Erlich S.
        • Pinkas-Kramarski R.
        Neuregulin rescues PC12-ErbB4 cells from cell death induced by H(2)O(2). Regulation of reactive oxygen species levels by phosphatidylinositol 3-kinase.
        J Biol Chem. 2001; 276: 46379-46385
        • Krishnan N.
        • Dickman M.B.
        • Becker D.F.
        Proline modulates the intracellular redox environment and protects mammalian cells against oxidative stress.
        Free Radic Biol Med. 2008; 44: 671-681
        • Otte D.M.
        • Sommersberg B.
        • Kudin A.
        • Guerrero C.
        • Albayram O.
        • Filiou M.D.
        • et al.
        N-acetyl cysteine treatment rescues cognitive deficits induced by mitochondrial dysfunction in G72/G30 transgenic mice.
        Neuropsychopharmacology. 2011; 36: 2233-2243
        • Park Y.U.
        • Jeong J.
        • Lee H.
        • Mun J.Y.
        • Kim J.H.
        • Lee J.S.
        • et al.
        Disrupted-in-schizophrenia 1 (DISC1) plays essential roles in mitochondria in collaboration with Mitofilin.
        Proc Natl Acad Sci U S A. 2010; 107: 17785-17790
        • Lewis D.A.
        • Levitt P.
        Schizophrenia is a disorder of neurodevelopment.
        Annu Rev Neurosci. 2002; 25: 409-432
        • Lewis D.A.
        • Curley A.A.
        • Glausier J.R.
        • Volk D.W.
        Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia.
        Trends Neurosci. 2012; 35: 57-67
        • Bartos M.
        • Vida I.
        • Jonas P.
        Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks.
        Nat Rev Neurosci. 2007; 8: 45-56
        • Sohal V.S.
        • Zhang F.
        • Yizhar O.
        • Deisseroth K.
        Parvalbumin neurons and gamma rhythms enhance cortical circuit performance.
        Nature. 2009; 459: 698-702
        • Whittington M.A.
        • Cunningham M.O.
        • LeBeau F.E.
        • Racca C.
        • Traub R.D.
        Multiple origins of the cortical gamma rhythm.
        Dev Neurobiol. 2011; 71: 92-106
        • Barr M.S.
        • Farzan F.
        • Tran L.C.
        • Chen R.
        • Fitzgerald P.B.
        • Daskalakis Z.J.
        Evidence for excessive frontal evoked gamma oscillatory activity in schizophrenia during working memory.
        Schizophr Res. 2010; 121: 146-152
        • Cho R.Y.
        • Konecky R.O.
        • Carter C.S.
        Impairments in frontal cortical gamma synchrony and cognitive control in schizophrenia.
        Proc Natl Acad Sci U S A. 2006; 103: 19878-19883
        • Spencer K.M.
        • Niznikiewicz M.A.
        • Shenton M.E.
        • McCarley R.W.
        Sensory-evoked gamma oscillations in chronic schizophrenia.
        Biol Psychiatry. 2008; 63: 744-747
        • Uhlhaas P.J.
        • Singer W.
        The development of neural synchrony and large-scale cortical networks during adolescence: Relevance for the pathophysiology of schizophrenia and neurodevelopmental hypothesis.
        Schizophr Bull. 2011; 37: 514-523
        • Brenhouse H.C.
        • Andersen S.L.
        Nonsteroidal anti-inflammatory treatment prevents delayed effects of early life stress in rats.
        Biol Psychiatry. 2011; 70: 434-440
        • Schiavone S.
        • Sorce S.
        • Dubois-Dauphin M.
        • Jaquet V.
        • Colaianna M.
        • Zotti M.
        • et al.
        Involvement of NOX2 in the development of behavioral and pathologic alterations in isolated rats.
        Biol Psychiatry. 2009; 66: 384-392
        • Harte M.K.
        • Powell S.B.
        • Swerdlow N.R.
        • Geyer M.A.
        • Reynolds G.P.
        Deficits in parvalbumin and calbindin immunoreactive cells in the hippocampus of isolation reared rats.
        J Neural Transm. 2007; 114: 893-898
        • Behrens M.M.
        • Ali S.S.
        • Dao D.N.
        • Lucero J.
        • Shekhtman G.
        • Quick K.L.
        • et al.
        Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase.
        Science. 2007; 318: 1645-1647
        • Do K.Q.
        • Trabesinger A.H.
        • Kirsten-Kruger M.
        • Lauer C.J.
        • Dydak U.
        • Hell D.
        • et al.
        Schizophrenia: Glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo.
        Eur J Neurosci. 2000; 12: 3721-3728
        • Gawryluk J.W.
        • Wang J.F.
        • Andreazza A.C.
        • Shao L.
        • Young L.T.
        Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders.
        Int J Neuropsychopharmacol. 2011; 14: 123-130
        • Wang J.F.
        • Shao L.
        • Sun X.
        • Young L.T.
        Increased oxidative stress in the anterior cingulate cortex of subjects with bipolar disorder and schizophrenia.
        Bipolar Disord. 2009; 11: 523-529
        • Hashimoto T.
        • Volk D.W.
        • Eggan S.M.
        • Mirnics K.
        • Pierri J.N.
        • Sun Z.
        • et al.
        Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia.
        J Neurosci. 2003; 23: 6315-6326
        • Beasley C.L.
        • Zhang Z.J.
        • Patten I.
        • Reynolds G.P.
        Selective deficits in prefrontal cortical GABAergic neurons in schizophrenia defined by the presence of calcium-binding proteins.
        Biol Psychiatry. 2002; 52: 708-715
        • Dell’Anna E.
        • Geloso M.C.
        • Magarelli M.
        • Molinari M.
        Development of GABA and calcium binding proteins immunoreactivity in the rat hippocampus following neonatal anoxia.
        Neurosci Lett. 1996; 211: 93-96
        • Jiang M.
        • Swann J.W.
        A role for L-type calcium channels in the maturation of parvalbumin-containing hippocampal interneurons.
        Neuroscience. 2005; 135: 839-850
        • Pangratz-Fuehrer S.
        • Hestrin S.
        Synaptogenesis of electrical and GABAergic synapses of fast-spiking inhibitory neurons in the neocortex.
        J Neurosci. 2011; 31: 10767-10775
        • Tseng K.Y.
        • O’Donnell P.
        Dopamine modulation of prefrontal cortical interneurons changes during adolescence.
        Cereb Cortex. 2007; 17: 1235-1240
        • Wang H.X.
        • Gao W.J.
        Development of calcium-permeable AMPA receptors and their correlation with NMDA receptors in fast-spiking interneurons of rat prefrontal cortex.
        J Physiol. 2010; 588: 2823-2838
        • Hartig W.
        • Brauer K.
        • Bigl V.
        • Bruckner G.
        Chondroitin sulfate proteoglycan-immunoreactivity of lectin-labeled perineuronal nets around parvalbumin-containing neurons.
        Brain Res. 1994; 635: 307-311
        • Kwok J.C.
        • Dick G.
        • Wang D.
        • Fawcett JW.
        Extracellular matrix and perineuronal nets in CNS repair.
        Dev Neurobiol. 2011; 71: 1073-1089
        • Duarte J.M.
        • Kulak A.
        • Gholam-Razaee M.M.
        • Cuenod M.
        • Gruetter R.
        • Do K.Q.
        N-acetylcysteine normalizes neurochemical changes in the glutathione-deficient schizophrenia mouse model during development.
        Biol Psychiatry. 2012; 71: 1006-1014
        • Steullet P.
        • Cabungcal J.H.
        • Kulak A.
        • Kraftsik R.
        • Chen Y.
        • Dalton T.P.
        • et al.
        Redox dysregulation affects the ventral but not dorsal hippocampus: Impairment of parvalbumin neurons, gamma oscillations, and related behaviors.
        J Neurosci. 2010; 30: 2547-2558
        • Tosic M.
        • Ott J.
        • Barral S.
        • Bovet P.
        • Deppen P.
        • Gheorghita F.
        • et al.
        Schizophrenia and oxidative stress: Glutamate cysteine ligase modifier as a susceptibility gene.
        Am J Hum Genet. 2006; 79: 586-592
        • Cohen R.A.
        • Grieve S.
        • Hoth K.F.
        • Paul R.H.
        • Sweet L.
        • Tate D.
        • et al.
        Early life stress and morphometry of the adult anterior cingulate cortex and caudate nuclei.
        Biol Psychiatry. 2006; 59: 975-982
        • Gos T.
        • Bock J.
        • Poeggel G.
        • Braun K.
        Stress-induced synaptic changes in the rat anterior cingulate cortex are dependent on endocrine developmental time windows.
        Synapse. 2008; 62: 229-232
        • Law A.J.
        • Pei Q.
        • Feldon J.
        • Pryce CR.
        • Harrison P.J.
        Gene expression in the anterior cingulate cortex and amygdala of adolescent marmoset monkeys following parental separations in infancy.
        Int J Neuropsychopharmacol. 2009; 12: 761-772
        • Thomaes K.
        • Dorrepaal E.
        • Draijer N.
        • de Ruiter M.B.
        • van Balkom A.J.
        • Smit J.H.
        • et al.
        Reduced anterior cingulate and orbitofrontal volumes in child abuse-related complex PTSD.
        J Clin Psychiatry. 2010; 71: 1636-1644
        • Fornito A.
        • Yücel M.
        • Dean B.
        • Wood S.J.
        • Pantelis C.
        Anatomical abnormalities of the anterior cingulate cortex in schizophrenia: Bridging the gap between neuroimaging and neuropathology.
        Schizophr Bull. 2009; 35: 973-993
        • Todtenkop M.S.
        • Vincent S.L.
        • Benes F.M.
        A cross-study meta-analysis and three-dimensional comparison of cell counting in the anterior cingulate cortex of schizophrenic and bipolar brain.
        Schizophr Res. 2005; 73: 79-89
        • Yang Y.
        • Dieter M.Z.
        • Chen Y.
        • Shertzer H.G.
        • Nebert D.W.
        • Dalton T.P.
        Initial characterization of the glutamate-cysteine ligase modifier subunit Gclm(-/-) knockout mouse. Novel model system for a severely compromised oxidative stress response.
        J Biol Chem. 2002; 277: 49446-49452
        • Atkuri K.R.
        • Mantovani J.J.
        • Herzenberg L.A.
        • Herzenberg L.A.
        N-acetylcysteine—a safe antidote for cysteine/glutathione deficiency.
        Curr Opin Pharmacol. 2007; 7: 355-359
        • Cabungcal J.H.
        • Nicolas D.
        • Kraftsik R.
        • Cuenod M.
        • Do K.Q.
        • Hornung J.P.
        Glutathione deficit during development induces anomalies in the rat anterior cingulate GABAergic neurons: Relevance to schizophrenia.
        Neurobiol Dis. 2006; 22: 624-637
        • Franklin B.J.
        • Paxinos G.
        The Mouse Brain in Stereotaxic Coordinates.
        3rd ed. Academic Press Elsevier, New York2008
        • Schmitz C.
        • Hof P.R.
        Design-based stereology in neuroscience.
        Neuroscience. 2005; 130: 813-831
        • Kasai H.
        Analysis of a form of oxidative DNA damage, 8-hydroxy-2’-deoxyguanosine, as a marker of cellular oxidative stress during carcinogenesis.
        Mutat Res. 1997; 387: 147-163
        • Cadet J.L.
        • Brannock C.
        Free radicals and the pathobiology of brain dopamine systems.
        Neurochem Int. 1998; 32: 117-131
        • Rabinovic A.D.
        • Hastings T.G.
        Role of endogenous glutathione in the oxidation of dopamine.
        J Neurochem. 1998; 71: 2071-2078
        • Feenstra M.G.
        • Vogel M.
        • Botterblom M.H.
        • Joosten R.N.
        • de Bruin J.P.
        Dopamine and noradrenaline efflux in the rat prefrontal cortex after classical aversive conditioning to an auditory cue.
        Eur J Neurosci. 2001; 13: 1051-1054
        • Lataster J.
        • Collip D.
        • Ceccarini J.
        • Haas D.
        • Booij L.
        • van O.J.
        • et al.
        Psychosocial stress is associated with in vivo dopamine release in human ventromedial prefrontal cortex: A positron emission tomography study using [(18)F]fallypride.
        Neuroimage. 2011; 58: 1081-1089
        • Rivera A.
        • Peňafiel A.
        • Megías M.
        • Agnati L.F.
        • López-Tèllez J.F.
        • Gago B.
        • et al.
        Cellular localization and distribution of dopamine D4 receptors in the rat cerebral cortex and their relationship with the cortical dopaminergic and noradrenergic nerve terminal networks.
        Neuroscience. 2008; 155: 997-1010
        • Jones D.P.
        • Go Y.M.
        Redox compartmentalization and cellular stress.
        Diabetes Obes Metab. 2010; 12: 116-125
        • Hasenstaub A.
        • Otte S.
        • Callaway E.
        • Sejnowski T.J.
        Metabolic cost as a unifying principle governing neuronal biophysics.
        Proc Natl Acad Sci U S A. 2010; 107: 12329-12334
      1. Cabungcal JH, Steullet P, Kraftsik R, Cuenod M, Do QK (2011): The perineuronal net protects parvalbumin-immunoreactive interneurons against oxidative stress: Relevance to schizophrenia. Meeting of the Society for Neuroscience, November 12-16, 2011, Washington, DC. Available at:www.sfn.org/AM2011/, Meeting Planner Abstract 679.26/DD15. Accessed October 29, 2012

        • Bruckner G.
        • Grosche J.
        Perineuronal nets show intrinsic patterns of extracellular matrix differentiation in organotypic slice cultures.
        Exp Brain Res. 2001; 137: 83-93
        • Dityatev A.
        • Bruckner G.
        • Dityateva G.
        • Grosche J.
        • Kleene R.
        • Schachner M.
        Activity-dependent formation and functions of chondroitin sulfate-rich extracellular matrix of perineuronal nets.
        Dev Neurobiol. 2007; 67: 570-588
        • Bull R.
        • Finkelstein J.P.
        • Humeres A.
        • Behrens M.I.
        • Hidalgo C.
        Effects of ATP, Mg2+, and redox agents on the Ca2+ dependence of RyR channels from rat brain cortex.
        Am J Physiol Cell Physiol. 2007; 293: C162-C171
        • Campbell D.L.
        • Stamler J.S.
        • Strauss H.C.
        Redox modulation of L-type calcium channels in ferret ventricular myocytes. Dual mechanism regulation by nitric oxide and S-nitrosothiols.
        J Gen Physiol. 1996; 108: 277-293
        • Choi Y.
        • Chen H.V.
        • Lipton S.A.
        Three pairs of cysteine residues mediate both redox and zn2+ modulation of the nmda receptor.
        J Neurosci. 2001; 21: 392-400
        • Joseph S.K.
        • Nakao S.K.
        • Sukumvanich S.
        Reactivity of free thiol groups in type-I inositol trisphosphate receptors.
        Biochem J. 2006; 393: 575-582
        • Steullet P.
        • Lavoie S.
        • Kraftsik R.
        • Guidi R.
        • Gysin R.
        • Cuenod M.
        • et al.
        A glutathione deficit alters dopamine modulation of L-type calcium channels via D2 and ryanodine receptors in neurons.
        Free Radic Biol Med. 2008; 44: 1042-1054
        • Powell S.B.
        • Sejnowski T.J.
        • Behrens M.M.
        Behavioral and neurochemical consequences of cortical oxidative stress on parvalbumin-interneuron maturation in rodent models of schizophrenia.
        Neuropharmacology. 2012; 62: 2322-2331
        • Mandal P.K.
        • Seiler A.
        • Perisic T.
        • Kolle P.
        • Banjac C.A.
        • Forster H.
        • et al.
        System x(c)- and thioredoxin reductase 1 cooperatively rescue glutathione deficiency.
        J Biol Chem. 2010; 285: 22244-22253
        • Potvin S.
        • Stip E.
        • Sepehry A.A.
        • Gendron A.
        • Bah R.
        • Kouassi E.
        Inflammatory cytokine alterations in schizophrenia: A systematic quantitative review.
        Biol Psychiatry. 2008; 63: 801-808
        • Saetre P.
        • Emilsson L.
        • Axelsson E.
        • Kreuger J.
        • Lindholm E.
        • Jazin E.
        Inflammation-related genes up-regulated in schizophrenia brains.
        BMC Psychiatry. 2007; 7: 46
        • Lederbogen F.
        • Kirsch P.
        • Haddad L.
        • Streit F.
        • Tost H.
        • Schuch P.
        • et al.
        City living and urban upbringing affect neural social stress processing in humans.
        Nature. 2011; 474: 498-501
        • Brown A.S.
        The environment and susceptibility to schizophrenia.
        Prog Neurobiol. 2011; 93: 23-58
        • Conus P.
        • Cotton S.
        • Schimmelmann B.G.
        • McGorry P.D.
        • Lambert M.
        Pretreatment and outcome correlates of sexual and physical trauma in an epidemiological cohort of first-episode psychosis patients.
        Schizophr Bull. 2010; 36: 1105-1114
        • Krabbendam L.
        • van Os J.
        Schizophrenia and urbanicity: A major environmental influence—conditional on genetic risk.
        Schizophr Bull. 2005; 31: 795-799
        • Schafer I.
        • Fisher H.L.
        Childhood trauma and posttraumatic stress disorder in patients with psychosis: Clinical challenges and emerging treatments.
        Curr Opin Psychiatry. 2011; 24: 514-518
        • Gysin R.
        • Kraftsik R.
        • Boulat O.
        • Bovet P.
        • Conus P.
        • Comte-Krieger E.
        • et al.
        Genetic dysregulation of glutathione synthesis predicts alteration of plasma thiol redox status in schizophrenia.
        Antioxid Redox Signal. 2011; 15: 2003-2010

      Linked Article

      • Erratum
        Biological PsychiatryVol. 74Issue 4
        • Preview
          A funding body was inadvertently left out of the acknowledgments in the article “Early-Life Insults Impair Parvalbumin Interneurons via Oxidative Stress: Reversal by N-Acetylcysteine” by Cabungcal et al. (2013;73:574–582). The acknowledgments should have included the NCCR Synapsy, as follows: “This work was supported by the Swiss National Science Foundation (#31-116689 to KQD and #310030_135736/1 to KQD and PS), the NCCR Synapsy, “Loterie Romande”, Damm-Etienne Foundation and Alamaya Foundation.”
        • Full-Text
        • PDF