Molecular determinants of dysregulated GABAergic gene expression in the prefrontal cortex of subjects with schizophrenia.
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.
Mellios
Nikolaos
N
Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01604, USA.
Huang
Hsien-Sung
HS
Baker
Stephen P
SP
Galdzicka
Marzena
M
Ginns
Edward
E
Akbarian
Schahram
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000235:genetics; D016022:Case-Control Studies; D002843:Chromatin / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D005838:Genotype; D006801:Humans; D007118:Immunoassay; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000096:biosynthesis; D008875:Middle Aged; D009478:Neuropeptide Y / Q000096:biosynthesis / Q000235:genetics; D010320:Parvalbumins / Q000096:biosynthesis / Q000235:genetics; D017397:Prefrontal Cortex / Q000378:metabolism*; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism*; D013004:Somatostatin / Q000096:biosynthesis / Q000235:genetics; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000235:genetics* / Q000502:physiology*
D019208:Brain-Derived Neurotrophic Factor; D002843:Chromatin; D035683:MicroRNAs; D009478:Neuropeptide Y; D010320:Parvalbumins; D013004:Somatostatin; D005680:gamma-Aminobutyric Acid; D012313:RNA