Archival ReportMolecular Determinants of Dysregulated GABAergic Gene Expression in the Prefrontal Cortex of Subjects with Schizophrenia
Section snippets
Postmortem Brains
A total of 40 postmortem brain samples from 20 subjects diagnosed with schizophrenia and 20 control subjects were used in this study. See Supplement 1 and Table 1 for more details.
BDNF Immunoassay
Protein was extracted with the mirVANA PARIS Kit (Ambion, Austin, Texas) according to manufacturer's instructions, and after centrifugation, the supernatants were used for estimation of total protein with BCA Micro-kit (Pierce, Rockford, Illinois). Brain-derived neurotrophic factor levels were essayed with
Altered Expression of GABAergic Transcripts in PFC of Subjects with Schizophrenia
To determine if the reported deficits in a subset of GABAergic transcripts in PFC of patients with schizophrenia (10, 11) could be recapitulated in our cohort of 20 matched pairs (Table 1), we measured with qRT-PCR mRNA levels for NPY, SST, and PV. Our results revealed significant deficits (NPY, PV) or a trend for decrease (SST) in mRNA levels of the schizophrenia subjects (Figure 1A–C). To rule out that these alterations were due to differences in the level of the normalization gene, B2M, we
Discussion
Using multiple approaches, we uncovered a regulatory cascade that is involved in dysregulated GABAergic gene expression in the prefrontal cortex of subjects with schizophrenia. Importantly, we showed that miR-195, a small RNA interacting with the 3' UTR of BDNF transcript (29), contributes to the regulation and variability of BDNF protein levels, which in turn influence the disease-related deficits in NPY and SST mRNAs. Interestingly, open chromatin-associated histone (H3-lysine 4) methylation
References (47)
Genetic causality in schizophrenia and bipolar disorder: Out with the old and in with the new
Curr Opin Genet Dev
(2008)- et al.
Neuropeptide deficits in schizophrenia vs.Alzheimer's disease cerebral cortex
Biol Psychiatry
(1996) - et al.
Brain-derived neurotrophic factor and neurotrophin 3 in schizophrenic psychoses
Schizophr Res
(2001) - et al.
The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function
Cell
(2003) MicroRNAs: Genomics, biogenesis, mechanism, and function
Cell
(2004)- et al.
Accurate molecular characterization of formalin-fixed, paraffin-embedded tissues by microRNA expression profiling
J Mol Diagn
(2008) - et al.
Critical factors in gene expression in postmortem human brain: Focus on studies in schizophrenia
Biol Psychiatry
(2006) - et al.
Prediction of mammalian microRNA targets
Cell
(2003) - et al.
Association between the G1001C polymorphism in the GRIN1 gene promoter region and schizophrenia
Biol Psychiatry
(2003) - et al.
Decrease of serotonin receptor 2C in schizophrenia brains identified by high-resolution mRNA expression analysis
Biol Psychiatry
(2003)
Hippocampal FGF-2 and FGFR1 mRNA expression in major depression, schizophrenia and bipolar disorder
Brain Res Bull
A polymorphism of the metabotropic glutamate receptor mGluR7 (GRM7) gene is associated with schizophrenia
Schizophr Res
Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: The SzGene database
Nat Genet
Prefrontal dysfunction in schizophrenia involves mixed-lineage leukemia 1-regulated histone methylation at GABAergic gene promoters
J Neurosci
Epigenetic regulation in psychiatric disorders
Nat Rev Neurosci
GABA neurons and the mechanisms of network oscillations: Implications for understanding cortical dysfunction in schizophrenia
Schizophr Bull
Postnatal development of prefrontal inhibitory circuits and the pathophysiology of cognitive dysfunction in schizophrenia
Ann N Y Acad Sci
Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics
Arch Gen Psychiatry
GABAergic dysfunction in schizophrenia and mood disorders as reflected by decreased levels of glutamic acid decarboxylase 65 and 67 kDa and Reelin proteins in cerebellum
Schizophr Res
Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: A postmortem brain study
Arch Gen Psychiatry
Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia
Mol Psychiatry
Impairments in frontal cortical gamma synchrony and cognitive control in schizophrenia
Proc Natl Acad Sci U S A
Abnormal neural synchrony in schizophrenia
J Neurosci
Cited by (0)
Authors NM and H-SH contributed equally to this work.