OBJECTIVE: Cognitive deficits of schizophrenia may be due at least in part to lower expression of the 67-kDa isoform of glutamic acid decarboxylase (GAD67), a key enzyme for GABA synthesis, in the dorsolateral prefrontal cortex of individuals with schizophrenia. However, little is known about the molecular regulation of lower cortical GAD67 levels in schizophrenia. The GAD67 promoter region contains a conserved Zif268 binding site, and Zif268 activation is accompanied by increased GAD67 expression. Thus, altered expression of the immediate early gene Zif268 may contribute to lower levels of GAD67 mRNA in the dorsolateral prefrontal cortex in schizophrenia. METHOD: The authors used polymerase chain reaction to quantify GAD67 and Zif268 mRNA levels in dorsolateral prefrontal cortex area 9 from 62 matched pairs of schizophrenia and healthy comparison subjects, and in situ hybridization to assess Zif268 expression at laminar and cellular levels of resolution. The effects of potentially confounding variables were assessed in human subjects, and the effects of antipsychotic treatments were tested in antipsychotic-exposed monkeys. The specificity of the Zif268 findings was assessed by quantifying mRNA levels for other immediate early genes. RESULTS: GAD67 and Zif268 mRNA levels were significantly lower and were positively correlated in the schizophrenia subjects. Both Zif268 mRNA-positive neuron density and Zif268 mRNA levels per neuron were significantly lower in the schizophrenia subjects. These findings were robust to the effects of the confounding variables examined and differed from other immediate early genes. CONCLUSIONS: Deficient Zif268 mRNA expression may contribute to lower cortical GAD67 levels in schizophrenia, suggesting a potential mechanistic basis for altered cortical GABA synthesis and impaired cognition in schizophrenia.
OBJECTIVE:Cognitive deficits of schizophrenia may be due at least in part to lower expression of the 67-kDa isoform of glutamic acid decarboxylase (GAD67), a key enzyme for GABA synthesis, in the dorsolateral prefrontal cortex of individuals with schizophrenia. However, little is known about the molecular regulation of lower cortical GAD67 levels in schizophrenia. The GAD67 promoter region contains a conserved Zif268 binding site, and Zif268 activation is accompanied by increased GAD67 expression. Thus, altered expression of the immediate early gene Zif268 may contribute to lower levels of GAD67 mRNA in the dorsolateral prefrontal cortex in schizophrenia. METHOD: The authors used polymerase chain reaction to quantify GAD67 and Zif268 mRNA levels in dorsolateral prefrontal cortex area 9 from 62 matched pairs of schizophrenia and healthy comparison subjects, and in situ hybridization to assess Zif268 expression at laminar and cellular levels of resolution. The effects of potentially confounding variables were assessed in human subjects, and the effects of antipsychotic treatments were tested in antipsychotic-exposed monkeys. The specificity of the Zif268 findings was assessed by quantifying mRNA levels for other immediate early genes. RESULTS:GAD67 and Zif268 mRNA levels were significantly lower and were positively correlated in the schizophrenia subjects. Both Zif268 mRNA-positive neuron density and Zif268 mRNA levels per neuron were significantly lower in the schizophrenia subjects. These findings were robust to the effects of the confounding variables examined and differed from other immediate early genes. CONCLUSIONS: Deficient Zif268 mRNA expression may contribute to lower cortical GAD67 levels in schizophrenia, suggesting a potential mechanistic basis for altered cortical GABA synthesis and impaired cognition in schizophrenia.
Authors: Takanori Hashimoto; David W Volk; Stephen M Eggan; Karoly Mirnics; Joseph N Pierri; Zhuoxin Sun; Allan R Sampson; David A Lewis Journal: J Neurosci Date: 2003-07-16 Impact factor: 6.167
Authors: F Zhang; P Halleux; L Arckens; W Vanduffel; L Van Brée; P Mailleux; F Vandesande; G A Orban; J J Vanderhaeghen Journal: Neurosci Lett Date: 1994-08-01 Impact factor: 3.046
Authors: Tonya M Gilbert; Nicole R Zürcher; Christine J Wu; Anisha Bhanot; Baileigh G Hightower; Minhae Kim; Daniel S Albrecht; Hsiao-Ying Wey; Frederick A Schroeder; Anais Rodriguez-Thompson; Thomas M Morin; Kamber L Hart; Amelia M Pellegrini; Misha M Riley; Changning Wang; Steven M Stufflebeam; Stephen J Haggarty; Daphne J Holt; Marco L Loggia; Roy H Perlis; Hannah E Brown; Joshua L Roffman; Jacob M Hooker Journal: J Clin Invest Date: 2018-12-10 Impact factor: 14.808
Authors: John F Enwright; Sowmya Sanapala; Aaron Foglio; Raissa Berry; Kenneth N Fish; David A Lewis Journal: Neuropsychopharmacology Date: 2016-02-12 Impact factor: 7.853
Authors: Menachem Fromer; Panos Roussos; Solveig K Sieberts; Jessica S Johnson; David H Kavanagh; Thanneer M Perumal; Douglas M Ruderfer; Edwin C Oh; Aaron Topol; Hardik R Shah; Lambertus L Klei; Robin Kramer; Dalila Pinto; Zeynep H Gümüş; A Ercument Cicek; Kristen K Dang; Andrew Browne; Cong Lu; Lu Xie; Ben Readhead; Eli A Stahl; Jianqiu Xiao; Mahsa Parvizi; Tymor Hamamsy; John F Fullard; Ying-Chih Wang; Milind C Mahajan; Jonathan M J Derry; Joel T Dudley; Scott E Hemby; Benjamin A Logsdon; Konrad Talbot; Towfique Raj; David A Bennett; Philip L De Jager; Jun Zhu; Bin Zhang; Patrick F Sullivan; Andrew Chess; Shaun M Purcell; Leslie A Shinobu; Lara M Mangravite; Hiroyoshi Toyoshiba; Raquel E Gur; Chang-Gyu Hahn; David A Lewis; Vahram Haroutunian; Mette A Peters; Barbara K Lipska; Joseph D Buxbaum; Eric E Schadt; Keisuke Hirai; Kathryn Roeder; Kristen J Brennand; Nicholas Katsanis; Enrico Domenici; Bernie Devlin; Pamela Sklar Journal: Nat Neurosci Date: 2016-09-26 Impact factor: 24.884