Mapping dopaminergic deficiencies in the substantia nigra/ventral tegmental area in schizophrenia

Abstract

Previous work from our laboratory showed deficits in tyrosine hydroxylase protein expression within the substantia nigra/ventral tegmental area (SN/VTA) in schizophrenia. However, little is known about the nature and specific location of these deficits within the SN/VTA. The present study had two aims: (1) test if tyrosine hydroxylase deficits could be explained as the result of neuronal loss; (2) assess if deficits in tyrosine hydroxylase are sub-region specific within the SN/VTA, and thus, could affect specific dopaminergic pathways. To achieve these objectives: (1) we obtained estimates of the number of dopaminergic neurons, total number of neurons, and their ratio in matched SN/VTA schizophrenia and control samples; (2) we performed a qualitative assessment in SN/VTA schizophrenia and control matched samples that were processed simultaneously for tyrosine hydroxylase immunohistochemistry. We did not find any significant differences in the total number of neurons, dopaminergic neurons, or their ratio. Our qualitative study of TH expression showed a conspicuous decrease in labeling of neuronal processes and cell bodies within the SN/VTA, which was sub-region specific. Dorsal diencephalic dopaminergic populations of the SN/VTA presented the most conspicuous decrease in TH labeling. These data support the existence of pathway-specific dopaminergic deficits that would affect the dopamine input to the cortex without significant neuronal loss. Interestingly, these findings support earlier reports of decreases in tyrosine hydroxylase labeling in the target areas for this dopaminergic input in the prefrontal and entorhinal cortex. Finally, our findings support that tyrosine hydroxylase deficits could contribute to the hypodopaminergic state observed in cortical areas in schizophrenia.

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Acknowledgments

The authors wish to thank the Maryland Brain Collection, University of Maryland School of Medicine for providing the samples used in this study. This work was supported by the National Institutes of Health (USA) grant R01MH066123-09 awarded to MMF, EPC and RCR.

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The authors do not have any conflict of interest to report.

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Correspondence to Emma Perez-Costas.

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M. Melendez-Ferro and E. Perez-Costas are equal contributors.

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Rice, M.W., Roberts, R.C., Melendez-Ferro, M. et al. Mapping dopaminergic deficiencies in the substantia nigra/ventral tegmental area in schizophrenia. Brain Struct Funct 221, 185–201 (2016). https://doi.org/10.1007/s00429-014-0901-y

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Keywords

  • Tyrosine hydroxylase
  • Immunohistochemistry
  • Mesocortical
  • Mesolimbic
  • Neuropathology
  • Neuropsychiatric disorders