Selective epigenetic alteration of layer I GABAergic neurons isolated from prefrontal cortex of schizophrenia patients using laser-assisted microdissection

• Published in: Molecular psychiatry Vol. 12; no. 4; pp. 385 - 397
• Main Authors: Ruzicka, W B, Zhubi, A, Veldic, M, Grayson, D R, Costa, E, Guidotti, A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2007; Nature Publishing Group
• Subjects: Adult; Adult and adolescent clinical studies; Behavioral Sciences; Biological and medical sciences; Biological Psychology; Bipolar disorder; Brain; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA methylation; DNA methyltransferase; DNMT1 protein; Epigenesis, Genetic - physiology; Epigenetics; Female; gamma-Aminobutyric Acid - metabolism; Gene expression; Glutamate Decarboxylase - metabolism; Glutamic acid; Humans; Hybridization; Interneurons; Isoenzymes - metabolism; Lasers; Male; Medical sciences; Medicine; Medicine & Public Health; Mental disorders; Microdissection - methods; Middle Aged; Neurons; Neurons - metabolism; Neurons - pathology; Neurosciences; original-article; Patients; Pharmacotherapy; Polymerase chain reaction; Prefrontal cortex; Prefrontal Cortex - pathology; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychoses; Pyramidal cells; Reelin protein; Reverse Transcriptase Polymerase Chain Reaction - methods; Reverse transcription; RNA, Messenger - biosynthesis; Schizophrenia; Schizophrenia - etiology; Schizophrenia - genetics; Schizophrenia - pathology; γ-Aminobutyric acid; United States > US; Chicago Illinois; reelin; laser-assisted microdissection; DNMT1; GAD; schizophrenia; epigenetics; Human; Central nervous system; Schizophrenia; Prefrontal cortex; GAD67; Encephalon; Psychosis; Reelin; Epigenesis; Gabaergic neuron
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/sj.mp.4001954

Among the most consistent results of studies of post-mortem brain tissue from schizophrenia patients (SZP) is the finding that in this disease, several genes expressed by GABAergic neurons are downregulated. This downregulation may be caused by hypermethylation of the relevant promoters in affected neurons. Indeed, increased numbers of GABAergic interneurons expressing DNA methyltransferase 1 (DNMT1) mRNA have been demonstrated in the prefrontal cortex (PFC) of SZP using in situ hybridization. The present study expands upon these findings using nested competitive reverse transcription-polymerase chain reaction combined with laser-assisted microdissection to quantitate the extent of DNMT1 mRNA overexpression in distinct populations of GABAergic neurons obtained from either layer I or layer V of the PFC of SZP. In a cohort of eight SZP and eight non-psychiatric subject (NPS) post-mortem BA9 tissue samples, DNMT1 mRNA was found to be selectively expressed in GABAergic interneurons and virtually absent in pyramidal neurons. DNMT1 mRNA expression was approximately threefold higher in GABAergic interneurons microdissected from layer I of SZP relative to the same neurons microdissected from NPS. GABAergic interneurons obtained from layer V of the same samples displayed no difference in DNMT1 mRNA expression between groups. In the same samples, the GABAergic neuron-specific glutamic acid-decarboxylase 67 (GAD 67 ) and reelin mRNAs were underexpressed twofold in GABAergic interneurons isolated from layer I of SZP relative to GABAergic interneurons microdissected from layer I of NPS, and unaltered in GABAergic interneurons of layer V. These findings implicate an epigenetically mediated layer I GABAergic dysfunction in the pathogenesis of schizophrenia, and suggest novel strategies for treatment of the disease.