Novel animal models for studying complex brain disorders

BAC-driven miRNA-mediated in vivo silencing of gene expression

K. A. Garbett, S. Horváth, P. J. Ebert, M. J. Schmidt, K. Lwin, A. Mitchell, P. Levitt, K. Mirnics

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

In schizophrenia, glutamic acid decarboxylase 1 (GAD1) disturbances are robust, consistently observed, cell-type specific and represent a core feature of the disease. In addition, neuropeptide Y (NPY), which is a phenotypic marker of a sub-population of GAD1-containing interneurons, has shown reduced expression in the prefrontal cortex in subjects with schizophrenia, suggesting that dysfunction of the NPY + cortical interneuronal sub-population might be a core feature of this devastating disorder. However, modeling gene expression disturbances in schizophrenia in a cell type-specific manner has been extremely challenging. To more closely mimic these molecular and cellular human post-mortem findings, we generated a transgenic mouse in which we downregulated GAD1 mRNA expression specifically in NPY + neurons. This novel, cell type-specific in vivo system for reducing gene expression uses a bacterial artificial chromosome (BAC) containing the NPY promoter-enhancer elements, the reporter molecule (eGFP) and a modified intron containing a synthetic microRNA (miRNA) targeted to GAD1. The animals of isogenic strains are generated rapidly, providing a new tool for better understanding the molecular disturbances in the GABAergic system observed in complex neuropsychiatric disorders such as schizophrenia. In the future, because of the small size of the silencing miRNAs combined with our BAC strategy, this method may be modified to allow generation of mice with simultaneous silencing of multiple genes in the same cells with a single construct, and production of splice-variant-specific knockdown animals.

Original languageEnglish
Pages (from-to)987-995
Number of pages9
JournalMolecular Psychiatry
Volume15
Issue number10
DOIs
Publication statusPublished - Oct 2010

Fingerprint

Bacterial Artificial Chromosomes
Glutamate Decarboxylase
Neuropeptide Y
Brain Diseases
MicroRNAs
Schizophrenia
Animal Models
Gene Expression
Gene Silencing
Interneurons
Prefrontal Cortex
Introns
Transgenic Mice
Population
Down-Regulation
Neurons
Messenger RNA

Keywords

  • BAC
  • GAD1
  • miRNA
  • NPY
  • schizophrenia
  • transgenic

ASJC Scopus subject areas

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

Cite this

Novel animal models for studying complex brain disorders : BAC-driven miRNA-mediated in vivo silencing of gene expression. / Garbett, K. A.; Horváth, S.; Ebert, P. J.; Schmidt, M. J.; Lwin, K.; Mitchell, A.; Levitt, P.; Mirnics, K.

In: Molecular Psychiatry, Vol. 15, No. 10, 10.2010, p. 987-995.

Research output: Contribution to journalArticle

Garbett, KA, Horváth, S, Ebert, PJ, Schmidt, MJ, Lwin, K, Mitchell, A, Levitt, P & Mirnics, K 2010, 'Novel animal models for studying complex brain disorders: BAC-driven miRNA-mediated in vivo silencing of gene expression', Molecular Psychiatry, vol. 15, no. 10, pp. 987-995. https://doi.org/10.1038/mp.2010.1
Garbett, K. A. ; Horváth, S. ; Ebert, P. J. ; Schmidt, M. J. ; Lwin, K. ; Mitchell, A. ; Levitt, P. ; Mirnics, K. / Novel animal models for studying complex brain disorders : BAC-driven miRNA-mediated in vivo silencing of gene expression. In: Molecular Psychiatry. 2010 ; Vol. 15, No. 10. pp. 987-995.
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