Locomotor hyperactivity in 14-3-3ζ KO mice is associated with dopamine transporter dysfunction

H. Ramshaw, X. Xu, E. J. Jaehne, P. McCarthy, Z. Greenberg, E. Saleh, B. McClure, J. Woodcock, S. Kabbara, S. Wiszniak, Ting Yi Wang, C. Parish, M. Van Den Buuse, B. T. Baune, A. Lopez, Q. Schwarz

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Dopamine (DA) neurotransmission requires a complex series of enzymatic reactions that are tightly linked to catecholamine exocytosis and receptor interactions on pre- and postsynaptic neurons. Regulation of dopaminergic signalling is primarily achieved through reuptake of extracellular DA by the DA transporter (DAT) on presynaptic neurons. Aberrant regulation of DA signalling, and in particular hyperactivation, has been proposed as a key insult in the presentation of schizophrenia and related neuropsychiatric disorders. We recently identified 14-3-3ζ as an essential component of neurodevelopment and a central risk factor in the schizophrenia protein interaction network. Our analysis of 14-3-3ζ-deficient mice now shows that baseline hyperactivity of knockout (KO) mice is rescued by the antipsychotic drug clozapine. 14-3-3ζ KO mice displayed enhanced locomotor hyperactivity induced by the DA releaser amphetamine. Consistent with 14-3-3ζ having a role in DA signalling, we found increased levels of DA in the striatum of 14-3-3ζ KO mice. Although 14-3-3ζ is proposed to modulate activity of the rate-limiting DA biosynthesis enzyme, tyrosine hydroxylase (TH), we were unable to identify any differences in total TH levels, TH localization or TH activation in 14-3-3ζ KO mice. Rather, our analysis identified significantly reduced levels of DAT in the absence of notable differences in RNA or protein levels of DA receptors D1-D5. Providing insight into the mechanisms by which 14-3-3ζ controls DAT stability, we found a physical association between 14-3-3ζ and DAT by co-immunoprecipitation. Taken together, our results identify a novel role for 14-3-3ζ in DA neurotransmission and provide support to the hyperdopaminergic basis of pathologies associated with schizophrenia and related disorders.

LanguageEnglish
Article numbere327
JournalTranslational Psychiatry
Volume3
DOIs
Publication statusPublished - 3 Dec 2013

Keywords

  • 14-3-3ζ
  • Dopamine neurotransmission
  • Dopamine transporter
  • Schizophrenia
  • Schizophrenia mouse model

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Biological Psychiatry

Cite this

Ramshaw, H. ; Xu, X. ; Jaehne, E. J. ; McCarthy, P. ; Greenberg, Z. ; Saleh, E. ; McClure, B. ; Woodcock, J. ; Kabbara, S. ; Wiszniak, S. ; Wang, Ting Yi ; Parish, C. ; Van Den Buuse, M. ; Baune, B. T. ; Lopez, A. ; Schwarz, Q. / Locomotor hyperactivity in 14-3-3ζ KO mice is associated with dopamine transporter dysfunction. In: Translational Psychiatry. 2013 ; Vol. 3.
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title = "Locomotor hyperactivity in 14-3-3ζ KO mice is associated with dopamine transporter dysfunction",
abstract = "Dopamine (DA) neurotransmission requires a complex series of enzymatic reactions that are tightly linked to catecholamine exocytosis and receptor interactions on pre- and postsynaptic neurons. Regulation of dopaminergic signalling is primarily achieved through reuptake of extracellular DA by the DA transporter (DAT) on presynaptic neurons. Aberrant regulation of DA signalling, and in particular hyperactivation, has been proposed as a key insult in the presentation of schizophrenia and related neuropsychiatric disorders. We recently identified 14-3-3ζ as an essential component of neurodevelopment and a central risk factor in the schizophrenia protein interaction network. Our analysis of 14-3-3ζ-deficient mice now shows that baseline hyperactivity of knockout (KO) mice is rescued by the antipsychotic drug clozapine. 14-3-3ζ KO mice displayed enhanced locomotor hyperactivity induced by the DA releaser amphetamine. Consistent with 14-3-3ζ having a role in DA signalling, we found increased levels of DA in the striatum of 14-3-3ζ KO mice. Although 14-3-3ζ is proposed to modulate activity of the rate-limiting DA biosynthesis enzyme, tyrosine hydroxylase (TH), we were unable to identify any differences in total TH levels, TH localization or TH activation in 14-3-3ζ KO mice. Rather, our analysis identified significantly reduced levels of DAT in the absence of notable differences in RNA or protein levels of DA receptors D1-D5. Providing insight into the mechanisms by which 14-3-3ζ controls DAT stability, we found a physical association between 14-3-3ζ and DAT by co-immunoprecipitation. Taken together, our results identify a novel role for 14-3-3ζ in DA neurotransmission and provide support to the hyperdopaminergic basis of pathologies associated with schizophrenia and related disorders.",
keywords = "14-3-3ζ, Dopamine neurotransmission, Dopamine transporter, Schizophrenia, Schizophrenia mouse model",
author = "H. Ramshaw and X. Xu and Jaehne, {E. J.} and P. McCarthy and Z. Greenberg and E. Saleh and B. McClure and J. Woodcock and S. Kabbara and S. Wiszniak and Wang, {Ting Yi} and C. Parish and {Van Den Buuse}, M. and Baune, {B. T.} and A. Lopez and Q. Schwarz",
year = "2013",
month = "12",
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Ramshaw, H, Xu, X, Jaehne, EJ, McCarthy, P, Greenberg, Z, Saleh, E, McClure, B, Woodcock, J, Kabbara, S, Wiszniak, S, Wang, TY, Parish, C, Van Den Buuse, M, Baune, BT, Lopez, A & Schwarz, Q 2013, 'Locomotor hyperactivity in 14-3-3ζ KO mice is associated with dopamine transporter dysfunction', Translational Psychiatry, vol. 3, e327. https://doi.org/10.1038/tp.2013.99

Locomotor hyperactivity in 14-3-3ζ KO mice is associated with dopamine transporter dysfunction. / Ramshaw, H.; Xu, X.; Jaehne, E. J.; McCarthy, P.; Greenberg, Z.; Saleh, E.; McClure, B.; Woodcock, J.; Kabbara, S.; Wiszniak, S.; Wang, Ting Yi; Parish, C.; Van Den Buuse, M.; Baune, B. T.; Lopez, A.; Schwarz, Q.

In: Translational Psychiatry, Vol. 3, e327, 03.12.2013.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Locomotor hyperactivity in 14-3-3ζ KO mice is associated with dopamine transporter dysfunction

AU - Ramshaw, H.

AU - Xu, X.

AU - Jaehne, E. J.

AU - McCarthy, P.

AU - Greenberg, Z.

AU - Saleh, E.

AU - McClure, B.

AU - Woodcock, J.

AU - Kabbara, S.

AU - Wiszniak, S.

AU - Wang, Ting Yi

AU - Parish, C.

AU - Van Den Buuse, M.

AU - Baune, B. T.

AU - Lopez, A.

AU - Schwarz, Q.

PY - 2013/12/3

Y1 - 2013/12/3

N2 - Dopamine (DA) neurotransmission requires a complex series of enzymatic reactions that are tightly linked to catecholamine exocytosis and receptor interactions on pre- and postsynaptic neurons. Regulation of dopaminergic signalling is primarily achieved through reuptake of extracellular DA by the DA transporter (DAT) on presynaptic neurons. Aberrant regulation of DA signalling, and in particular hyperactivation, has been proposed as a key insult in the presentation of schizophrenia and related neuropsychiatric disorders. We recently identified 14-3-3ζ as an essential component of neurodevelopment and a central risk factor in the schizophrenia protein interaction network. Our analysis of 14-3-3ζ-deficient mice now shows that baseline hyperactivity of knockout (KO) mice is rescued by the antipsychotic drug clozapine. 14-3-3ζ KO mice displayed enhanced locomotor hyperactivity induced by the DA releaser amphetamine. Consistent with 14-3-3ζ having a role in DA signalling, we found increased levels of DA in the striatum of 14-3-3ζ KO mice. Although 14-3-3ζ is proposed to modulate activity of the rate-limiting DA biosynthesis enzyme, tyrosine hydroxylase (TH), we were unable to identify any differences in total TH levels, TH localization or TH activation in 14-3-3ζ KO mice. Rather, our analysis identified significantly reduced levels of DAT in the absence of notable differences in RNA or protein levels of DA receptors D1-D5. Providing insight into the mechanisms by which 14-3-3ζ controls DAT stability, we found a physical association between 14-3-3ζ and DAT by co-immunoprecipitation. Taken together, our results identify a novel role for 14-3-3ζ in DA neurotransmission and provide support to the hyperdopaminergic basis of pathologies associated with schizophrenia and related disorders.

AB - Dopamine (DA) neurotransmission requires a complex series of enzymatic reactions that are tightly linked to catecholamine exocytosis and receptor interactions on pre- and postsynaptic neurons. Regulation of dopaminergic signalling is primarily achieved through reuptake of extracellular DA by the DA transporter (DAT) on presynaptic neurons. Aberrant regulation of DA signalling, and in particular hyperactivation, has been proposed as a key insult in the presentation of schizophrenia and related neuropsychiatric disorders. We recently identified 14-3-3ζ as an essential component of neurodevelopment and a central risk factor in the schizophrenia protein interaction network. Our analysis of 14-3-3ζ-deficient mice now shows that baseline hyperactivity of knockout (KO) mice is rescued by the antipsychotic drug clozapine. 14-3-3ζ KO mice displayed enhanced locomotor hyperactivity induced by the DA releaser amphetamine. Consistent with 14-3-3ζ having a role in DA signalling, we found increased levels of DA in the striatum of 14-3-3ζ KO mice. Although 14-3-3ζ is proposed to modulate activity of the rate-limiting DA biosynthesis enzyme, tyrosine hydroxylase (TH), we were unable to identify any differences in total TH levels, TH localization or TH activation in 14-3-3ζ KO mice. Rather, our analysis identified significantly reduced levels of DAT in the absence of notable differences in RNA or protein levels of DA receptors D1-D5. Providing insight into the mechanisms by which 14-3-3ζ controls DAT stability, we found a physical association between 14-3-3ζ and DAT by co-immunoprecipitation. Taken together, our results identify a novel role for 14-3-3ζ in DA neurotransmission and provide support to the hyperdopaminergic basis of pathologies associated with schizophrenia and related disorders.

KW - 14-3-3ζ

KW - Dopamine neurotransmission

KW - Dopamine transporter

KW - Schizophrenia

KW - Schizophrenia mouse model

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U2 - 10.1038/tp.2013.99

DO - 10.1038/tp.2013.99

M3 - Article

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JF - Translational Psychiatry

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