Loss of Function Studies in Mice and Genetic Association Link Receptor Protein Tyrosine Phosphatase a to Schizophrenia

Nagahide Takahashi; Karin Sandager Nielsen; Branko Aleksic; Steffen Petersen; Masashi Ikeda; Itaru Kushima; Nathalie Vacaresse; Hiroshi Ujike; Nakao Iwata; Véronique Dubreuil; Naheed Mirza; Takeshi Sakurai; Norio Ozaki; Joseph D Buxbaum; Jan Sap

doi:10.1016/j.biopsych.2011.06.016

Loss of Function Studies in Mice and Genetic Association Link Receptor Protein Tyrosine Phosphatase a to Schizophrenia

Nagahide Takahashi, Karin Sandager Nielsen, Branko Aleksic, Steffen Petersen, Masashi Ikeda, Itaru Kushima, Nathalie Vacaresse, Hiroshi Ujike, Nakao Iwata, Véronique Dubreuil, Naheed Mirza, Takeshi Sakurai, Norio Ozaki, Joseph D Buxbaum, Jan Sap

Department of Biomedical Sciences

17 Citations (Scopus)

Abstract

Background: Solid evidence links schizophrenia (SZ) susceptibility to neurodevelopmental processes involving tyrosine phosphorylation-mediated signaling. Mouse studies implicate the Ptpra gene, encoding protein tyrosine phosphatase RPTPα, in the control of radial neuronal migration, cortical cytoarchitecture, and oligodendrocyte differentiation. The human gene encoding RPTPα, PTPRA, maps to a chromosomal region (20p13) associated with susceptibility to psychotic illness. Methods: We characterized neurobehavioral parameters, as well as gene expression in the central nervous system, of mice with a null mutation in the Ptpra gene. We searched for genetic association between polymorphisms in PTPRA and schizophrenia risk (two independent cohorts, 1420 cases and 1377 controls), and we monitored PTPRA expression in prefrontal dorsolateral cortex of SZ patients (35 cases, 2 control groups of 35 cases). Results: We found that Ptpra ^-/- mice reproduce neurobehavioral endophenotypes of human SZ: sensitization to methamphetamine-induced hyperactivity, defective sensorimotor gating, and defective habituation to a startle response. Ptpra loss of function also leads to reduced expression of multiple myelination genes, mimicking the hypomyelination-associated changes in gene expression observed in postmortem patient brains. We further report that a polymorphism at the PTPRA locus is genetically associated with SZ, and that PTPRA mRNA levels are reduced in postmortem dorsolateral prefrontal cortex of subjects with SZ. Conclusions: The implication of this well-studied signaling protein in SZ risk and endophenotype manifestation provides novel entry points into the etiopathology of this disease.

Original language	English
Journal	Biological Psychiatry
Volume	70
Issue number	7
Pages (from-to)	626-35
Number of pages	10
ISSN	0006-3223
DOIs	https://doi.org/10.1016/j.biopsych.2011.06.016
Publication status	Published - 1 Oct 2011

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Takahashi, N., Nielsen, K. S., Aleksic, B., Petersen, S., Ikeda, M., Kushima, I., Vacaresse, N., Ujike, H., Iwata, N., Dubreuil, V., Mirza, N., Sakurai, T., Ozaki, N., Buxbaum, J. D., & Sap, J. (2011). Loss of Function Studies in Mice and Genetic Association Link Receptor Protein Tyrosine Phosphatase a to Schizophrenia. Biological Psychiatry, 70(7), 626-35. https://doi.org/10.1016/j.biopsych.2011.06.016

Takahashi, N, Nielsen, KS, Aleksic, B, Petersen, S, Ikeda, M, Kushima, I, Vacaresse, N, Ujike, H, Iwata, N, Dubreuil, V, Mirza, N, Sakurai, T, Ozaki, N, Buxbaum, JD & Sap, J 2011, 'Loss of Function Studies in Mice and Genetic Association Link Receptor Protein Tyrosine Phosphatase a to Schizophrenia', Biological Psychiatry, vol. 70, no. 7, pp. 626-35. https://doi.org/10.1016/j.biopsych.2011.06.016

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title = "Loss of Function Studies in Mice and Genetic Association Link Receptor Protein Tyrosine Phosphatase a to Schizophrenia",

abstract = "Background: Solid evidence links schizophrenia (SZ) susceptibility to neurodevelopmental processes involving tyrosine phosphorylation-mediated signaling. Mouse studies implicate the Ptpra gene, encoding protein tyrosine phosphatase RPTPα, in the control of radial neuronal migration, cortical cytoarchitecture, and oligodendrocyte differentiation. The human gene encoding RPTPα, PTPRA, maps to a chromosomal region (20p13) associated with susceptibility to psychotic illness. Methods: We characterized neurobehavioral parameters, as well as gene expression in the central nervous system, of mice with a null mutation in the Ptpra gene. We searched for genetic association between polymorphisms in PTPRA and schizophrenia risk (two independent cohorts, 1420 cases and 1377 controls), and we monitored PTPRA expression in prefrontal dorsolateral cortex of SZ patients (35 cases, 2 control groups of 35 cases). Results: We found that Ptpra -/- mice reproduce neurobehavioral endophenotypes of human SZ: sensitization to methamphetamine-induced hyperactivity, defective sensorimotor gating, and defective habituation to a startle response. Ptpra loss of function also leads to reduced expression of multiple myelination genes, mimicking the hypomyelination-associated changes in gene expression observed in postmortem patient brains. We further report that a polymorphism at the PTPRA locus is genetically associated with SZ, and that PTPRA mRNA levels are reduced in postmortem dorsolateral prefrontal cortex of subjects with SZ. Conclusions: The implication of this well-studied signaling protein in SZ risk and endophenotype manifestation provides novel entry points into the etiopathology of this disease.",

author = "Nagahide Takahashi and Nielsen, {Karin Sandager} and Branko Aleksic and Steffen Petersen and Masashi Ikeda and Itaru Kushima and Nathalie Vacaresse and Hiroshi Ujike and Nakao Iwata and V{\'e}ronique Dubreuil and Naheed Mirza and Takeshi Sakurai and Norio Ozaki and Buxbaum, {Joseph D} and Jan Sap",

year = "2011",

month = oct,

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doi = "10.1016/j.biopsych.2011.06.016",

language = "English",

volume = "70",

pages = "626--35",

journal = "Biological Psychiatry",

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T1 - Loss of Function Studies in Mice and Genetic Association Link Receptor Protein Tyrosine Phosphatase a to Schizophrenia

AU - Takahashi, Nagahide

AU - Nielsen, Karin Sandager

AU - Aleksic, Branko

AU - Petersen, Steffen

AU - Ikeda, Masashi

AU - Kushima, Itaru

AU - Vacaresse, Nathalie

AU - Ujike, Hiroshi

AU - Iwata, Nakao

AU - Dubreuil, Véronique

AU - Mirza, Naheed

AU - Sakurai, Takeshi

AU - Ozaki, Norio

AU - Buxbaum, Joseph D

AU - Sap, Jan

PY - 2011/10/1

Y1 - 2011/10/1

N2 - Background: Solid evidence links schizophrenia (SZ) susceptibility to neurodevelopmental processes involving tyrosine phosphorylation-mediated signaling. Mouse studies implicate the Ptpra gene, encoding protein tyrosine phosphatase RPTPα, in the control of radial neuronal migration, cortical cytoarchitecture, and oligodendrocyte differentiation. The human gene encoding RPTPα, PTPRA, maps to a chromosomal region (20p13) associated with susceptibility to psychotic illness. Methods: We characterized neurobehavioral parameters, as well as gene expression in the central nervous system, of mice with a null mutation in the Ptpra gene. We searched for genetic association between polymorphisms in PTPRA and schizophrenia risk (two independent cohorts, 1420 cases and 1377 controls), and we monitored PTPRA expression in prefrontal dorsolateral cortex of SZ patients (35 cases, 2 control groups of 35 cases). Results: We found that Ptpra -/- mice reproduce neurobehavioral endophenotypes of human SZ: sensitization to methamphetamine-induced hyperactivity, defective sensorimotor gating, and defective habituation to a startle response. Ptpra loss of function also leads to reduced expression of multiple myelination genes, mimicking the hypomyelination-associated changes in gene expression observed in postmortem patient brains. We further report that a polymorphism at the PTPRA locus is genetically associated with SZ, and that PTPRA mRNA levels are reduced in postmortem dorsolateral prefrontal cortex of subjects with SZ. Conclusions: The implication of this well-studied signaling protein in SZ risk and endophenotype manifestation provides novel entry points into the etiopathology of this disease.

AB - Background: Solid evidence links schizophrenia (SZ) susceptibility to neurodevelopmental processes involving tyrosine phosphorylation-mediated signaling. Mouse studies implicate the Ptpra gene, encoding protein tyrosine phosphatase RPTPα, in the control of radial neuronal migration, cortical cytoarchitecture, and oligodendrocyte differentiation. The human gene encoding RPTPα, PTPRA, maps to a chromosomal region (20p13) associated with susceptibility to psychotic illness. Methods: We characterized neurobehavioral parameters, as well as gene expression in the central nervous system, of mice with a null mutation in the Ptpra gene. We searched for genetic association between polymorphisms in PTPRA and schizophrenia risk (two independent cohorts, 1420 cases and 1377 controls), and we monitored PTPRA expression in prefrontal dorsolateral cortex of SZ patients (35 cases, 2 control groups of 35 cases). Results: We found that Ptpra -/- mice reproduce neurobehavioral endophenotypes of human SZ: sensitization to methamphetamine-induced hyperactivity, defective sensorimotor gating, and defective habituation to a startle response. Ptpra loss of function also leads to reduced expression of multiple myelination genes, mimicking the hypomyelination-associated changes in gene expression observed in postmortem patient brains. We further report that a polymorphism at the PTPRA locus is genetically associated with SZ, and that PTPRA mRNA levels are reduced in postmortem dorsolateral prefrontal cortex of subjects with SZ. Conclusions: The implication of this well-studied signaling protein in SZ risk and endophenotype manifestation provides novel entry points into the etiopathology of this disease.

U2 - 10.1016/j.biopsych.2011.06.016

DO - 10.1016/j.biopsych.2011.06.016

M3 - Journal article

C2 - 21831360

SN - 0006-3223

VL - 70

SP - 626

EP - 635

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 7

ER -

Loss of Function Studies in Mice and Genetic Association Link Receptor Protein Tyrosine Phosphatase a to Schizophrenia

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