Molecular Determinants of Dysregulated GABAergic Gene Expression in the Prefrontal Cortex of Subjects with Schizophrenia

• Published in: Biological psychiatry (1969) Vol. 65; no. 12; pp. 1006 - 1014
• Main Authors: Mellios, Nikolaos, Huang, Hsien-Sung, Baker, Stephen P., Galdzicka, Marzena, Ginns, Edward, Akbarian, Schahram
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 15.06.2009; Elsevier
• Subjects: Adult; Adult and adolescent clinical studies; Aged; Aged, 80 and over; Animals; BDNF; Biological and medical sciences; Brain-Derived Neurotrophic Factor - biosynthesis; Brain-Derived Neurotrophic Factor - genetics; Case-Control Studies; Chromatin - genetics; gamma-Aminobutyric Acid - genetics; gamma-Aminobutyric Acid - physiology; Gene Expression Regulation - physiology; Genotype; Humans; Immunoassay; Immunoprecipitation; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; microRNAs; MicroRNAs - biosynthesis; Middle Aged; Neuropeptide Y - biosynthesis; Neuropeptide Y - genetics; NPY; Parvalbumins - biosynthesis; Parvalbumins - genetics; prefrontal cortex; Prefrontal Cortex - metabolism; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychoses; RNA - biosynthesis; RNA - isolation & purification; Schizophrenia; Schizophrenia - genetics; Schizophrenia - metabolism; Somatostatin - biosynthesis; Somatostatin - genetics; SST; Young Adult; microRNAs; schizophrenia; BDNF; SST; NPY; prefrontal cortex; Human; Neuropeptide Y; Peptide hormone; Central nervous system; Schizophrenia; Prefrontal cortex; Gene expression; Genetic determinism; Encephalon; Psychosis; Genetics; Brain derived neurotrophic factor
• ISSN: 0006-3223; 1873-2402; 1873-2402
• DOI: 10.1016/j.biopsych.2008.11.019

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. 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. 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. 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.