Role of glutamic acid decarboxylase 67 in regulating cortical parvalbumin and GABA membrane transporter 1 expression: Implications for schizophrenia
Markers of GABA neurotransmission are altered in multiple regions of the neocortex in individuals with schizophrenia. Lower levels of glutamic acid decarboxylase 67 (GAD67) mRNA and protein, which is responsible for most cortical GABA synthesis, are accompanied by lower levels of GABA membrane trans...
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| Format: | Article |
| Language: | English |
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Elsevier
2013-02-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996112003464 |
| _version_ | 1818870023433748480 |
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| author | Allison A. Curley Stephen M. Eggan Matt S. Lazarus Z. Josh Huang David W. Volk David A. Lewis |
| author_facet | Allison A. Curley Stephen M. Eggan Matt S. Lazarus Z. Josh Huang David W. Volk David A. Lewis |
| author_sort | Allison A. Curley |
| collection | DOAJ |
| description | Markers of GABA neurotransmission are altered in multiple regions of the neocortex in individuals with schizophrenia. Lower levels of glutamic acid decarboxylase 67 (GAD67) mRNA and protein, which is responsible for most cortical GABA synthesis, are accompanied by lower levels of GABA membrane transporter 1 (GAT1) mRNA. These alterations are thought to be most prominent in the parvalbumin (PV)-containing subclass of interneurons, which also contain lower levels of PV mRNA. Since GAT1 and PV each reduce the availability of GABA at postsynaptic receptors, lower levels of GAT1 and PV mRNAs have been hypothesized to represent compensatory responses to an upstream reduction in cortical GABA synthesis in schizophrenia. However, such cause-and-effect hypotheses cannot be directly tested in a human illness. Consequently, we used two mouse models with reduced GAD67 expression specifically in PV neurons (PVGAD67+/−) or in all interneurons (GABAGAD67+/−) and quantified GAD67, GAT1 and PV mRNA levels using methods identical to those employed in studies of schizophrenia. Cortical levels of PV or GAT1 mRNAs were not altered in PVGAD67+/− mice during postnatal development or in adulthood. Furthermore, cellular analyses confirmed the predicted reduction in GAD67 mRNA, but failed to show a deficit in PV mRNA in these animals. Levels of PV and GAT1 mRNAs were also unaltered in GABAGAD67+/− mice. Thus, mouse lines with cortical reductions in GAD67 mRNA that match or exceed those present in schizophrenia, and that differ in the developmental timing and cell type-specificity of the GAD67 deficit, failed to provide proof-of-concept evidence that lower PV and GAT1 expression in schizophrenia are a consequence of lower GAD67 expression. Together, these findings suggest that the correlated decrements in cortical GAD67, PV and GAT1 mRNAs in schizophrenia may be a common consequence of some other upstream factor. |
| first_indexed | 2024-12-19T12:00:26Z |
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| id | doaj.art-274da3c6e2bf42148748a65671eeabe2 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-19T12:00:26Z |
| publishDate | 2013-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-274da3c6e2bf42148748a65671eeabe22022-12-21T20:22:31ZengElsevierNeurobiology of Disease1095-953X2013-02-0150179186Role of glutamic acid decarboxylase 67 in regulating cortical parvalbumin and GABA membrane transporter 1 expression: Implications for schizophreniaAllison A. Curley0Stephen M. Eggan1Matt S. Lazarus2Z. Josh Huang3David W. Volk4David A. Lewis5Department of Psychiatry, W1653 Biomedical Science Tower, 200 Lothrop St. University of Pittsburgh, Pittsburgh, PA 15213, USADepartment of Psychiatry, W1653 Biomedical Science Tower, 200 Lothrop St. University of Pittsburgh, Pittsburgh, PA 15213, USACold Spring Harbor Laboratory, 1 Bungtown Rd Cold Spring Harbor, NY 11724, USACold Spring Harbor Laboratory, 1 Bungtown Rd Cold Spring Harbor, NY 11724, USADepartment of Psychiatry, W1653 Biomedical Science Tower, 200 Lothrop St. University of Pittsburgh, Pittsburgh, PA 15213, USADepartment of Psychiatry, W1653 Biomedical Science Tower, 200 Lothrop St. University of Pittsburgh, Pittsburgh, PA 15213, USA; Corresponding author at: Department of Psychiatry, W1653 Biomedical Science Tower, 200 Lothrop St., University of Pittsburgh, Pittsburgh, PA 15213, USA.Markers of GABA neurotransmission are altered in multiple regions of the neocortex in individuals with schizophrenia. Lower levels of glutamic acid decarboxylase 67 (GAD67) mRNA and protein, which is responsible for most cortical GABA synthesis, are accompanied by lower levels of GABA membrane transporter 1 (GAT1) mRNA. These alterations are thought to be most prominent in the parvalbumin (PV)-containing subclass of interneurons, which also contain lower levels of PV mRNA. Since GAT1 and PV each reduce the availability of GABA at postsynaptic receptors, lower levels of GAT1 and PV mRNAs have been hypothesized to represent compensatory responses to an upstream reduction in cortical GABA synthesis in schizophrenia. However, such cause-and-effect hypotheses cannot be directly tested in a human illness. Consequently, we used two mouse models with reduced GAD67 expression specifically in PV neurons (PVGAD67+/−) or in all interneurons (GABAGAD67+/−) and quantified GAD67, GAT1 and PV mRNA levels using methods identical to those employed in studies of schizophrenia. Cortical levels of PV or GAT1 mRNAs were not altered in PVGAD67+/− mice during postnatal development or in adulthood. Furthermore, cellular analyses confirmed the predicted reduction in GAD67 mRNA, but failed to show a deficit in PV mRNA in these animals. Levels of PV and GAT1 mRNAs were also unaltered in GABAGAD67+/− mice. Thus, mouse lines with cortical reductions in GAD67 mRNA that match or exceed those present in schizophrenia, and that differ in the developmental timing and cell type-specificity of the GAD67 deficit, failed to provide proof-of-concept evidence that lower PV and GAT1 expression in schizophrenia are a consequence of lower GAD67 expression. Together, these findings suggest that the correlated decrements in cortical GAD67, PV and GAT1 mRNAs in schizophrenia may be a common consequence of some other upstream factor.http://www.sciencedirect.com/science/article/pii/S0969996112003464Glutamic acid decarboxylaseGABA transporterParvalbuminPrefrontal cortexSchizophrenia |
| spellingShingle | Allison A. Curley Stephen M. Eggan Matt S. Lazarus Z. Josh Huang David W. Volk David A. Lewis Role of glutamic acid decarboxylase 67 in regulating cortical parvalbumin and GABA membrane transporter 1 expression: Implications for schizophrenia Neurobiology of Disease Glutamic acid decarboxylase GABA transporter Parvalbumin Prefrontal cortex Schizophrenia |
| title | Role of glutamic acid decarboxylase 67 in regulating cortical parvalbumin and GABA membrane transporter 1 expression: Implications for schizophrenia |
| title_full | Role of glutamic acid decarboxylase 67 in regulating cortical parvalbumin and GABA membrane transporter 1 expression: Implications for schizophrenia |
| title_fullStr | Role of glutamic acid decarboxylase 67 in regulating cortical parvalbumin and GABA membrane transporter 1 expression: Implications for schizophrenia |
| title_full_unstemmed | Role of glutamic acid decarboxylase 67 in regulating cortical parvalbumin and GABA membrane transporter 1 expression: Implications for schizophrenia |
| title_short | Role of glutamic acid decarboxylase 67 in regulating cortical parvalbumin and GABA membrane transporter 1 expression: Implications for schizophrenia |
| title_sort | role of glutamic acid decarboxylase 67 in regulating cortical parvalbumin and gaba membrane transporter 1 expression implications for schizophrenia |
| topic | Glutamic acid decarboxylase GABA transporter Parvalbumin Prefrontal cortex Schizophrenia |
| url | http://www.sciencedirect.com/science/article/pii/S0969996112003464 |
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