Title

Molecular determinants of dysregulated GABAergic gene expression in the prefrontal cortex of subjects with schizophrenia

UMMS Affiliation

Department of Psychiatry; Information Services, Academic Computing Services; Department of Cell Biology

Date

1-6-2009

Document Type

Article

Subjects

Adult; Aged; Aged, 80 and over; Animals; Brain-Derived Neurotrophic Factor; Case-Control Studies; Chromatin; Gene Expression Regulation; Genotype; Humans; Immunoassay; Immunoprecipitation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; Middle Aged; Neuropeptide Y; Parvalbumins; Prefrontal Cortex; RNA; Schizophrenia; Somatostatin; Young Adult; gamma-Aminobutyric Acid

Disciplines

Life Sciences | Medicine and Health Sciences | Neuroscience and Neurobiology | Psychiatry

Abstract

BACKGROUND: Prefrontal deficits in gamma-aminobutyric acid (GABA)ergic gene expression, including neuropeptide Y (NPY), somatostatin (SST), and parvalbumin (PV) messenger RNAs (mRNAs), have been reported for multiple schizophrenia cohorts. Preclinical models suggest that a subset of these GABAergic markers (NPY/SST) is regulated by brain-derived neurotrophic factor (BDNF), which in turn is under the inhibitory influence of small noncoding RNAs. However, it remains unclear if these mechanisms are important determinants for dysregulated NPY and SST expression in prefrontal cortex (PFC) of subjects with schizophrenia.

METHODS: Using a postmortem case-control design, the association between BDNF protein, NPY/SST/PV mRNAs, and two BDNF-regulating microRNAs (miR-195 and miR-30a-5p) was determined in samples from the PFC of 20 schizophrenia and 20 control subjects. Complementary studies were conducted in cerebral cortex of mice subjected to antipsychotic treatment or a brain-specific ablation of the Bdnf gene.

RESULTS: Subjects with schizophrenia showed deficits in NPY and PV mRNAs. Within-pair differences in BDNF protein levels showed strong positive correlations with NPY and SST and a robust inverse association with miR-195 levels, which in turn were not affected by antipsychotic treatment or genetic ablation of Bdnf.

CONCLUSIONS: Taken together, these results suggest that prefrontal deficits in a subset of GABAergic mRNAs, including NPY, are dependent on the regional supply of BDNF, which in turn is fine-tuned through a microRNA (miRNA)-mediated mechanism.

Rights and Permissions

Citation: Biol Psychiatry. 2009 Jun 15;65(12):1006-14. Epub 2009 Jan 1. Link to article on publisher's site

Comments

Co-authors Nikolaos Mellios and Hsien-Sung Huang are students in the Neuroscience program in the Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.

Related Resources

Link to Article in PubMed

PubMed ID

19121517