title: Chemokine receptors and cortical interneuron dysfunction in schizophrenia.
abstract: Alterations in inhibitory (GABA) neurons, including deficiencies in the GABA synthesizing enzyme GAD67, in the prefrontal cortex in schizophrenia are pronounced in the subpopulations of neurons that contain the calcium-binding protein parvalbumin or the neuropeptide somatostatin. The presence of similar illness-related deficits in the transcription factor Lhx6, which regulates prenatal development of parvalbumin and somatostatin neurons, suggests that cortical GABA neuron dysfunction may be related to disturbances in utero. Since the chemokine receptors CXCR4 and CXCR7 guide the migration of cortical parvalbumin and somatostatin neurons from their birthplace in the medial ganglionic eminence to their final destination in the neocortex, we sought to determine whether altered CXCR4 and/or CXCR7 mRNA levels were associated with disturbances in GABA-related markers in schizophrenia. Quantitative PCR was used to quantify CXCR4 and CXCR7 mRNA levels in the prefrontal cortex of 62 schizophrenia and 62 healthy comparison subjects that were previously characterized for markers of parvalbumin and somatostatin neurons and in antipsychotic-exposed monkeys. We found elevated mRNA levels for CXCR7 (+29%; p<.0001) and CXCR4 (+14%, p=.052) in schizophrenia subjects but not in antipsychotic-exposed monkeys. CXCR7 mRNA levels were inversely correlated with mRNA levels for GAD67, parvalbumin, somatostatin, and Lhx6 in schizophrenia but not in healthy subjects. These findings suggest that higher mRNA levels for CXCR7, and possibly CXCR4, may represent a compensatory mechanism to sustain the migration and correct positioning of cortical parvalbumin and somatostatin neurons in the face of other insults that disrupt the prenatal development of cortical GABA neurons in schizophrenia.
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: Anjani
authors.initials: A
authors.lastname: Chitrapu
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: D000328:Adult; D000704:Analysis of Variance; D005260:Female; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007395:Interneurons / Q000473:pathology*; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010320:Parvalbumins / Q000235:genetics / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D054387:Receptors, CXCR / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D012559:Schizophrenia / Q000473:pathology*; D013004:Somatostatin / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: C501896:ACKR3 protein, human; C527276:CXCR4 protein, human; C121947:LHX6 protein, human; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins; D010320:Parvalbumins; D012333:RNA, Messenger; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; D014157:Transcription Factors; D013004:Somatostatin; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1
keywords: GABA; GAD67; Parvalbumin; Postmortem; Prenatal development; Somatostatin