title: Altered expression of developmental regulators of parvalbumin and somatostatin neurons in the prefrontal cortex in schizophrenia.
abstract: Dysfunction of prefrontal cortex (PFC) inhibitory neurons that express the calcium-binding protein parvalbumin or the neuropeptide somatostatin in schizophrenia may be related to disturbances in the migration, phenotypic specification, and/or maturation of these neurons. These pre- and postnatal developmental stages are regulated in a cell type-specific manner by various transcription factors and co-activators, fibroblast growth factor receptors (FgfR), and other molecular markers. Consequently, we used quantitative PCR to quantify mRNA levels for these developmental regulators in the PFC of 62 schizophrenia subjects in whom parvalbumin and somatostatin neuron disturbances were previously reported, and in antipsychotic-exposed monkeys. Relative to unaffected comparison subjects, subjects with schizophrenia exhibited elevated mRNA levels for 1) the transcription factor MafB, which is expressed by parvalbumin and somatostatin neurons as they migrate from the medial ganglionic eminence to the cortex, 2) the transcriptional coactivator PGC-1α, which is expressed postnatally by parvalbumin neurons to maintain parvalbumin levels and inhibitory function, and 3) FgfR1, which is required for the migration and phenotypic specification of parvalbumin and somatostatin neurons. Elevations in these markers were most prominent in younger schizophrenia subjects and were not present in antipsychotic-exposed monkeys. Finally, expression levels of other important developmental regulators (i.e. Dlx1, Dlx5, Dlx6, SATB1, Sip1/Zeb2, ST8SIA4, cMaf, Nkx6.2, and Arx) were not altered in schizophrenia. The over-expression of a subset of molecular markers with distinct roles in the pre- and postnatal development of parvalbumin and somatostatin neurons might reflect compensatory mechanisms to sustain the development of these neurons in the face of other insults.
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, United States. Electronic address: volkdw@upmc.edu.
authors.forename: David W
authors.initials: DW
authors.lastname: Volk
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, United States.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Edelson
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, United States; Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15213, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Lewis
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001569:Benzodiazepines / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006220:Haloperidol / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008252:Macaca fascicularis; D051258:MafB Transcription Factor / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D000077152:Olanzapine; D010320:Parvalbumins / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism*; D013004:Somatostatin / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; C490407:MAFB protein, human; D051258:MafB Transcription Factor; C486497:PPARGC1A protein, human; D010320:Parvalbumins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger; D001569:Benzodiazepines; D013004:Somatostatin; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D006220:Haloperidol; D000077152:Olanzapine
keywords: GABA; Inhibitory; Ontogeny; Postmortem; Prenatal