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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

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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.

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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.

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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.

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  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

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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.

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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

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