Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Thalamic reticular nucleus impairments and abnormal prefrontal control of dopamine system in a developmental model of schizophrenia: prevention by N-acetylcysteine

Molecular Psychiatry volume 26, pages 7679–7689 (2021)Cite this article

Subjects

Abstract

Recent evidence showed thalamic abnormalities in schizophrenia involving disruptions to the parvalbumin neurons in the thalamic reticular nucleus (TRN). However, their functional consequences, as well as a potential linkage to oxidative stress, are unclear. The TRN is posited to gate prefrontal control of dopamine neuron activity in the ventral tegmental area (VTA). Thus, we hypothesized that schizophrenia-related TRN abnormalities might contribute to dopamine dysregulation, a well-known feature of the disorder. To test this, in adult rats exposed prenatally to methylazoxymethanol acetate (MAM rats), oxidative impairments to the parvalbumin neurons in the anterior TRN were assessed by immunohistochemistry. Using in vivo electrophysiology, we investigated whether inactivation of the prefrontal cortex would produce differential effects on VTA dopamine neurons in MAM rats. We show that MAM rats displayed reduced markers of parvalbumin and wisteria floribunda agglutinin-labeled perineuronal nets, correlating with increased markers of oxidative stress (8-oxo-7, 8-dihydro-20-deoxyguanosine, and 3-nitrotyrosine). Moreover, MAM rats displayed heightened baseline and abnormal prefrontal control of VTA dopamine neuron activity, as tetrodotoxin-induced inactivation of the infralimbic prefrontal cortex decreased the dopamine population activity, contrary to the normal increase in controls. Such dopamine neuron dysregulation was recapitulated by enzymatic perineuronal net digestion in the TRN of normal rats. Furthermore, juvenile (postnatal day 11–25) antioxidant treatment (N-acetyl-cysteine, 900 mg/L drinking water) prevented all these impairments in MAM rats. Our findings suggest that early accumulation of oxidative stress in the TRN may shape the later onset of schizophrenia pathophysiology, highlighting redox regulation as a potential target for early intervention.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Oxidative stress-induced PV and PNN circuitry impairment in the anterior segment of TRN in adult MAM rats was prevented by juvenile N-acetylcysteine (NAC) treatment.
Fig. 2: Population activity and ilPFC control of VTA dopamine neurons were altered in MAM rats.
Fig. 3: Enhanced baseline activity and abnormal prefrontal control of VTA dopamine neurons were prevented by P11−25 NAC oral treatment.
Fig. 4: ChABC-induced PNN degradation in the TRN recapitulated MAM-like phenotypes in the prefrontal control of VTA dopamine neurons.
Fig. 5: Schematics of the proposed pathways mediating the differential effects of ilPFC inactivation on VTA dopamine neurons in SAL vs. MAM rats.

Similar content being viewed by others

References

  1. Marín O. Interneuron dysfunction in psychiatric disorders. Nat Rev Neurosci. 2012;13:107–20.

    Article  PubMed  Google Scholar 

  2. Steullet P, Cabungcal JH, Coyle J, Didriksen M, Gill K, Grace AA, et al. Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia. Mol Psychiatry. 2017;22:936–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Gonzalez-Burgos G, Cho RY, Lewis DA. Alterations in cortical network oscillations and parvalbumin neurons in schizophrenia. Biol Psychiatry. 2015;77:1031–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Nakazawa K, Zsiros V, Jiang Z, Nakao K, Kolata S, Zhang S. et al. GABAergic interneuron origin of schizophrenia pathophysiology. Neuropharmacology. 2012;62:1574–83.

    Article  CAS  PubMed  Google Scholar 

  5. Perkins DO, Jeffries CD, Do KQ. Potential roles of redox dysregulation in the development of schizophrenia. Biol Psychiatry. 2020;88:326−336.

  6. Kann O, Papageorgiou IE, Draguhn A. Highly energized inhibitory interneurons are a central element for information processing in cortical networks. J Cereb Blood Flow Metab. 2014;34:1270–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Do KQ, Cabungcal JH, Frank A, Steullet P, Cuenod M. Redox dysregulation, neurodevelopment, and schizophrenia. Curr Opin Neurobiol. 2009;19:220–30.

    Article  CAS  PubMed  Google Scholar 

  8. Flatow J, Buckley P, Miller BJ. Meta-analysis of oxidative stress in schizophrenia. Biol Psychiatry. 2013;74:400–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Emiliani FE, Sedlak TW, Sawa A. Oxidative stress and schizophrenia: recent breakthroughs from an old story. Curr Opin Psychiatry. 2014;27:185–90.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Kulak A, Steullet P, Cabungcal J-H, Werge T, Ingason A, Cuenod M, et al. Redox dysregulation in the pathophysiology of schizophrenia and bipolar disorder: insights from animal models. Antioxid Redox Signal. 2013;18:1428–43.

    Article  CAS  PubMed  Google Scholar 

  11. 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 USA 2007;104:16621–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kulak A, Cuenod M, Do KQ. Behavioral phenotyping of glutathione-deficient mice: relevance to schizophrenia and bipolar disorder. Behavioural Brain Res. 2012;226:563–70.

    Article  CAS  Google Scholar 

  13. Cabungcal J-H, Preissmann D, Delseth C, Cuénod M, Do KQ, Schenk F. Transitory glutathione deficit during brain development induces cognitive impairment in juvenile and adult rats: relevance to schizophrenia. Neurobiol Dis. 2007;26:634–45.

    Article  CAS  PubMed  Google Scholar 

  14. 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;64:361–8.

    Article  CAS  PubMed  Google Scholar 

  15. Conus P, Seidman LJ, Fournier M, Xin L, Cleusix M, Baumann PS, et al. N-acetylcysteine in a double-blind randomized placebo-controlled trial: toward biomarker-guided treatment in early psychosis. Schizophrenia Bull. 2018;44:317–27.

    Article  Google Scholar 

  16. Millan MJ, Andrieux A, Bartzokis G, Cadenhead K, Dazzan P, Fusar-Poli P, et al. Altering the course of schizophrenia: progress and perspectives. Nat Rev Drug Discov. 2016;15:485.

    Article  CAS  PubMed  Google Scholar 

  17. Steullet P. Thalamus-related anomalies as candidate mechanism-based biomarkers for psychosis. Schizophr Res. 2019;226:147−157.

  18. Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature 2007;445:168–76.

    Article  CAS  PubMed  Google Scholar 

  19. Csillik B, Mihály A, Krisztin-Péva B, Chadaide Z, Samsam M, Knyihár-Csillik E, et al. GABAergic parvalbumin-immunoreactive large calyciform presynaptic complexes in the reticular nucleus of the rat thalamus. J Chem Neuroanat. 2005;30:17–26.

    Article  CAS  PubMed  Google Scholar 

  20. Cabungcal JH, Steullet P, Kraftsik R, Cuenod M, Do KQ. A developmental redox dysregulation leads to spatio-temporal deficit of parvalbumin neuron circuitry in a schizophrenia mouse model. Schizophr Res. 2019;213:96–106.

    Article  PubMed  Google Scholar 

  21. Steullet P, Cabungcal J-H, Bukhari SA, Ardelt MI, Pantazopoulos H, Hamati F, et al. The thalamic reticular nucleus in schizophrenia and bipolar disorder: role of parvalbumin-expressing neuron networks and oxidative stress. Mol Psychiatry. 2018;23:2057–65.

    Article  CAS  PubMed  Google Scholar 

  22. Crabtree JW. Functional diversity of thalamic reticular subnetworks. Front Syst Neurosci. 2018;12:41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Krol A, Wimmer RD, Halassa MM, Feng G. Thalamic reticular dysfunction as a circuit endophenotype in neurodevelopmental disorders. Neuron 2018;98:282–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pratt JA, Morris BJ. The thalamic reticular nucleus: a functional hub for thalamocortical network dysfunction in schizophrenia and a target for drug discovery. J Psychopharmacol. 2015;29:127–37.

    Article  PubMed  Google Scholar 

  25. Ferrarelli F, Tononi G. The thalamic reticular nucleus and schizophrenia. Schizophr Bull. 2011;37:306–15.

    Article  PubMed  Google Scholar 

  26. You Q-L, Luo Z-c, Luo Z-Y, Kong Y, Li Z-l, Yang J-M, et al. Involvement of the thalamic reticular nucleus in prepulse inhibition of acoustic startle. Transl Psychiatry. 2021;11:241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Richard EA, Khlestova E, Nanu R, Lisman JE. Potential synergistic action of 19 schizophrenia risk genes in the thalamus. Schizophrenia Res. 2017;180:64–9.

    Article  Google Scholar 

  28. Tomitaka S, Tomitaka M, Tolliver BK, Sharp FR. Bilateral blockade of NMDA receptors in anterior thalamus by dizocilpine (MK‐801) injures pyramidal neurons in rat retrosplenial cortex. Eur J Neurosci. 2000;12:1420–30.

    Article  CAS  PubMed  Google Scholar 

  29. Sharp FR, Tomitaka M, Bernaudin M, Tomitaka S. Psychosis: pathological activation of limbic thalamocortical circuits by psychomimetics and schizophrenia? Trends Neurosci. 2001;24:330–4.

    Article  CAS  PubMed  Google Scholar 

  30. Cochran SM, Kennedy M, McKerchar CE, Steward LJ, Pratt JA, Morris BJ. Induction of metabolic hypofunction and neurochemical deficits after chronic intermittent exposure to phencyclidine: differential modulation by antipsychotic drugs. Neuropsychopharmacology 2003;28:265–75.

    Article  CAS  PubMed  Google Scholar 

  31. Steullet P, Cabungcal J-H, Kulak A, Kraftsik R, Chen Y, Dalton TP, et al. Redox dysregulation affects the ventral but not dorsal hippocampus: impairment of parvalbumin neurons, gamma oscillations, and related behaviors. J Neurosci. 2010;30:2547–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Grace AA. Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression. Nat Rev Neurosci. 2016;17:524–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Grace AA. Dopamine system dysregulation by the hippocampus: Implications for the pathophysiology and treatment of schizophrenia. Neuropharmacology. 2012;62:1342–8.

    Article  CAS  PubMed  Google Scholar 

  34. Lieberman JA, Girgis RR, Brucato G, Moore H, Provenzano F, Kegeles L, et al. Hippocampal dysfunction in the pathophysiology of schizophrenia: a selective review and hypothesis for early detection and intervention. Mol Psychiatry. 2018;23:1764–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lewis DA, Curley AA, Glausier JR, Volk DW. Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci. 2012;35:57–67.

    Article  CAS  PubMed  Google Scholar 

  36. Patton MH, Bizup BT, Grace AA. The infralimbic cortex bidirectionally modulates mesolimbic dopamine neuron activity via distinct neural pathways. J Neurosci. 2013;33:16865–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Vertes RP. Differential projections of the infralimbic and prelimbic cortex in the rat. Synapse 2004;51:32–58.

    Article  CAS  PubMed  Google Scholar 

  38. Zimmerman EC, Grace AA. Prefrontal cortex modulates firing pattern in the nucleus reuniens of the midline thalamus via distinct corticothalamic pathways. Eur J Neurosci. 2018;48:3255–72.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Zimmerman EC, Grace AA. The nucleus reuniens of the midline thalamus gates prefrontal-hippocampal modulation of ventral tegmental area dopamine neuron activity. J Neurosci. 2016;36:8977–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Modinos G, Allen P, Grace AA, McGuire P. Translating the MAM model of psychosis to humans. Trends Neurosci. 2015;38:129–38.

    Article  CAS  PubMed  Google Scholar 

  41. Sawa A, Seidman LJ. Is prophylactic psychiatry around the corner? Combating adolescent oxidative stress for adult psychosis and schizophrenia. Neuron 2014;83:991–3.

    Article  CAS  PubMed  Google Scholar 

  42. Perez SM, Donegan JJ, Lodge DJ. Effect of estrous cycle on schizophrenia-like behaviors in MAM exposed rats. Behav Brain Res. 2019;362:258–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Moore H, Jentsch JD, Ghajarnia M, Geyer MA, Grace AA. A neurobehavioral systems analysis of adult rats exposed to methylazoxymethanol acetate on E17: implications for the neuropathology of schizophrenia. Biol Psychiatry. 2006;60:253–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cabungcal J-H, Counotte DS, Lewis EM, Tejeda HA, Piantadosi P, Pollock C, et al. Juvenile antioxidant treatment prevents adult deficits in a developmental model of schizophrenia. Neuron 2014;83:1073–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. das Neves Duarte JM, Kulak A, Gholam-Razaee MM, Cuenod M, Gruetter R, Do KQ. N-acetylcysteine normalizes neurochemical changes in the glutathione-deficient schizophrenia mouse model during development. Biol Psychiatry. 2012;71:1006–14.

    Article  PubMed  Google Scholar 

  46. Cabungcal J-H, Steullet P, Kraftsik R, Cuenod M, Do KQ. Early-life insults impair parvalbumin interneurons via oxidative stress: reversal by N-acetylcysteine. Biol Psychiatry. 2013;73:574–82.

    Article  CAS  PubMed  Google Scholar 

  47. Ungless MA, Grace AA. Are you or aren’t you? Challenges associated with physiologically identifying dopamine neurons. Trends Neurosci. 2012;35:422–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Klein PM, Lu AC, Harper ME, McKown HM, Morgan JD, Beenhakker MP. Tenuous inhibitory GABAergic signaling in the reticular thalamus. J Neurosci. 2018;38:1232–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Balmer TS. Perineuronal nets enhance the excitability of fast-spiking neurons. eNeuro 2016;3:4.

    Article  Google Scholar 

  50. Moreines JL, Owrutsky ZL, Grace AA. Involvement of infralimbic prefrontal cortex but not lateral habenula in dopamine attenuation after chronic mild stress. Neuropsychopharmacology 2017;42:904–13.

    Article  CAS  PubMed  Google Scholar 

  51. Cabungcal JH, Steullet P, Morishita H, Kraftsik R, Cuenod M, Hensch TK, et al. Perineuronal nets protect fast-spiking interneurons against oxidative stress. Proceedings of the National Academy of Sciences. 2013;110:9130–5.

  52. Lodge DJ, Grace AA. Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia. J Neurosci. 2007;27:11424–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Lodge DJ, Behrens MM, Grace AA. A loss of parvalbumin-containing interneurons is associated with diminished oscillatory activity in an animal model of schizophrenia. J Neurosci. 2009;29:2344–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Lodge DJ. The MAM rodent model of schizophrenia. Current protocols in neuroscience. 2013;63:9–43.

  55. Do KQ, Cuenod M, Hensch TK. Targeting oxidative stress and aberrant critical period plasticity in the developmental trajectory to schizophrenia. Schizophrenia Bull. 2015;41:835–46.

    Article  Google Scholar 

  56. Reyes-Madrigal F, León-Ortiz P, Mao X, Mora-Durán R, Shungu DC, de la Fuente-Sandoval C. Striatal glutathione in first-episode psychosis patients measured in vivo with proton magnetic resonance spectroscopy. Arch Med Res. 2019;50:207–13.

    Article  CAS  PubMed  Google Scholar 

  57. Das TK, Javadzadeh A, Dey A, Sabesan P, Théberge J, Radua J, et al. Antioxidant defense in schizophrenia and bipolar disorder: a meta-analysis of MRS studies of anterior cingulate glutathione. Prog Neuro-Psychopharmacol Biol Psychiatry. 2019;91:94–102.

    Article  CAS  Google Scholar 

  58. Do KQ, Trabesinger AH, Kirsten-Krüger M, Lauer CJ, Dydak U, Hell D, et al. Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo. Eur J Neurosci. 2000;12:3721–8.

    Article  CAS  PubMed  Google Scholar 

  59. Kumar J, Liddle EB, Fernandes CC, Palaniyappan L, Hall EL, Robson SE, et al. Glutathione and glutamate in schizophrenia: a 7T MRS study. Molecular Psychiatry. 2020;25:873–82.

  60. Nucifora L, Tanaka T, Hayes L, Kim M, Lee B, Matsuda T, et al. Reduction of plasma glutathione in psychosis associated with schizophrenia and bipolar disorder in translational psychiatry. Transl Psychiatry 2017;7:e1215–e.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wang AM, Pradhan S, Coughlin JM, Trivedi A, DuBois SL, Crawford JL, et al. Assessing brain metabolism with 7-T proton magnetic resonance spectroscopy in patients with first-episode psychosis. JAMA Psychiatry. 2019;76:314–23.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Fonnum F, Lock E. The contributions of excitotoxicity, glutathione depletion and DNA repair in chemically induced injury to neurones: exemplified with toxic effects on cerebellar granule cells. J Neurochem. 2004;88:513–31.

    Article  CAS  PubMed  Google Scholar 

  63. Gomes FV, Zhu X, Grace AA. Stress during critical periods of development and risk for schizophrenia. Schizophrenia Res. 2019;213:107–13.

    Article  Google Scholar 

  64. Möller M, Du Preez JL, Emsley R, Harvey BH. Isolation rearing-induced deficits in sensorimotor gating and social interaction in rats are related to cortico-striatal oxidative stress, and reversed by sub-chronic clozapine administration. Eur Neuropsychopharmacol. 2011;21:471–83.

    Article  PubMed  Google Scholar 

  65. Schiavone S, Colaianna M, Curtis L. Impact of early life stress on the pathogenesis of mental disorders: relation to brain oxidative stress. Curr Pharm Des. 2015;21:1404–12.

    Article  CAS  PubMed  Google Scholar 

  66. Zimmerman EC, Bellaire M, Ewing SG, Grace AA. Abnormal stress responsivity in a rodent developmental disruption model of schizophrenia. Neuropsychopharmacology 2013;38:2131–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Phensy A, Duzdabanian HE, Brewer S, Panjabi A, Driskill C, Berz A, et al. Antioxidant treatment with N-acetyl cysteine prevents the development of cognitive and social behavioral deficits that result from perinatal ketamine treatment. Front Behav Neurosci. 2017;11:106.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Otte D-M, Sommersberg B, Kudin A, Guerrero C, Albayram Ö, Filiou MD, et al. N-acetyl cysteine treatment rescues cognitive deficits induced by mitochondrial dysfunction in G72/G30 transgenic mice. Neuropsychopharmacology 2011;36:2233–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Meister A. Glutathione biosynthesis and its inhibition. Methods Enzymol. 1995;252:26–30.

  70. Majak K, Berdel B, Kowiański P, Dziewiatkowski J, Lipowska M, Moryś J. Parvalbumin immunoreactivity changes in the thalamic reticular nucleus during the maturation of the rat’s brain. Folia Neuropathol. 1998;36:7–14.

    CAS  PubMed  Google Scholar 

  71. Mitrofanis J. Patterns of antigenic expression in the thalamic reticular nucleus of developing rats. J Comp Neurol. 1992;320:161–81.

    Article  CAS  PubMed  Google Scholar 

  72. Hou G, Smith AG, Zhang ZW. Lack of intrinsic GABAergic connections in the thalamic reticular nucleus of the mouse. J Neurosci: Off J Soc Neurosci. 2016;36:7246–52.

    Article  CAS  Google Scholar 

  73. Zikopoulos B, Barbas H. Prefrontal projections to the thalamic reticular nucleus form a unique circuit for attentional mechanisms. J Neurosci. 2006;26:7348–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Halassa MM, Acsády L. Thalamic inhibition: diverse sources, diverse scales. Trends Neurosci. 2016;39:680–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Cornwall J, Cooper J, Phillipson O. Projections to the rostral reticular thalamic nucleus in the rat. Exp Brain Res. 1990;80:157–71.

    Article  CAS  PubMed  Google Scholar 

  76. Kolmac CI, Mitrofanis J. Organisation of the reticular thalamic projection to the intralaminar and midline nuclei in rats. J Comp Neurol. 1997;377:165–78.

    Article  CAS  PubMed  Google Scholar 

  77. Varela C, Kumar S, Yang JY, Wilson MA. Anatomical substrates for direct interactions between hippocampus, medial prefrontal cortex, and the thalamic nucleus reuniens. Brain Struct Funct. 2014;219:911–29.

    Article  CAS  PubMed  Google Scholar 

  78. McKenna JT, Vertes RP. Afferent projections to nucleus reuniens of the thalamus. J Comp Neurol. 2004;480:115–42.

    Article  PubMed  Google Scholar 

  79. Sherman, S. & Guillery, R. Functional Connections of Cortical Areas: A New View from the Thalamus. Chapter 4, Classification of Afferents in Thalamus and Cortex; Cambridge, MA: The MIT Press. 2013. p.83–118.

  80. Paz JT, Bryant AS, Peng K, Fenno L, Yizhar O, Frankel WN, et al. A new mode of corticothalamic transmission revealed in the Gria4(−/−) model of absence epilepsy. Nat Neurosci. 2011;14:1167–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Crandall SR, Cruikshank SJ, Connors BW. A corticothalamic switch: controlling the thalamus with dynamic synapses. Neuron 2015;86:768–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Warren RA, Agmon A, Jones EG. Oscillatory synaptic interactions between ventroposterior and reticular neurons in mouse thalamus in vitro. J Neurophysiol. 1994;72:1993–2003.

    Article  CAS  PubMed  Google Scholar 

  83. Woodward ND, Heckers S. Mapping thalamocortical functional connectivity in chronic and early stages of psychotic disorders. Biol Psychiatry. 2016;79:1016–25.

    Article  PubMed  Google Scholar 

  84. Pantazopoulos H, Woo T-UW, Lim MP, Lange N, Berretta S. Extracellular matrix-glial abnormalities in the amygdala and entorhinal cortex of subjects diagnosed with schizophrenia. Arch Gen Psychiatry. 2010;67:155–66.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Aldini G, Altomare A, Baron G, Vistoli G, Carini M, Borsani L, et al. N-Acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why. Free Radic Res. 2018;52:751–62.

    Article  CAS  PubMed  Google Scholar 

  86. Shah A, Lodge DJ. A loss of hippocampal perineuronal nets produces deficits in dopamine system function: relevance to the positive symptoms of schizophrenia. Transl Psychiatry 2013;3:e215-e.

    Article  Google Scholar 

  87. Alemán‐Gómez Y, Najdenovska E, Roine T, Fartaria MJ, Canales‐Rodríguez EJ, Rovó Z, et al. Partial‐volume modeling reveals reduced gray matter in specific thalamic nuclei early in the time course of psychosis and chronic schizophrenia. Hum Brain Mapp. 2020;41:4041–61.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work is supported by the National Institutes of Health (NIH MH57440 to AAG). We thank Niki MacMurdo and Dr. Rudolf Kraftsik for the technical assistance. We acknowledge funding support from the National Center of Competence in Research (NCCR) “SYNAPSY—The Synaptic Bases of Mental Diseases” from the Swiss National Science Foundation (n° 51AU40_125759 to KQD), Damm-Etienne Foundation, and Alamaya Foundation.

Author information

Author notes

  1. These authors contributed equally: Xiyu Zhu, Jan-Harry Cabungcal.

  2. These authors jointly supervised this work: Kim Q. Do, Anthony A. Grace.

Authors and Affiliations

  1. Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA

    Xiyu Zhu, Daniela L. Uliana & Anthony A. Grace

  2. Center for Psychiatric Neuroscience, Lausanne University Hospital-CHUV, Prilly-Lausanne, Switzerland

    Jan-Harry Cabungcal, Michel Cuenod & Kim Q. Do

  3. Department of Psychiatry, Lausanne University Hospital-CHUV, Prilly-Lausanne, Switzerland

    Jan-Harry Cabungcal, Michel Cuenod & Kim Q. Do

  4. Departments of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

    Anthony A. Grace

  5. Department of Psychology, University of Pittsburgh, Pittsburgh, PA, USA

    Anthony A. Grace

Authors
  1. Xiyu Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jan-Harry Cabungcal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michel Cuenod
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Daniela L. Uliana
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kim Q. Do
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anthony A. Grace
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiyu Zhu.

Ethics declarations

Competing interests

AAG has received funds from Lundbeck, Pfizer, Otsuka, Lilly, Roche, Asubio, Abbott, Autofony, Janssen, Alkermes, Newron, Takeda, Concert, and Minerva. KQD received an investigator-initiated research grant from Boehringer Ingelheim outside the current study. No other disclosures were reported.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhu, X., Cabungcal, JH., Cuenod, M. et al. Thalamic reticular nucleus impairments and abnormal prefrontal control of dopamine system in a developmental model of schizophrenia: prevention by N-acetylcysteine. Mol Psychiatry 26, 7679–7689 (2021). https://doi.org/10.1038/s41380-021-01198-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-021-01198-8

This article is cited by

Search

Advanced search

Quick links