title: Cortical parvalbumin GABAergic deficits with α7 nicotinic acetylcholine receptor deletion: implications for schizophrenia.
abstract: Dysfunction of cortical parvalbumin (PV)-containing GABAergic interneurons has been implicated in cognitive deficits of schizophrenia. In humans microdeletion of the CHRNA7 (α7 nicotinic acetylcholine receptor, nAChR) gene is associated with cortical dysfunction in a broad spectrum of neurodevelopmental and neuropsychiatric disorders including schizophrenia while in mice similar deletion causes analogous abnormalities including impaired attention, working-memory and learning. However, the pathophysiological roles of α7 nAChRs in cortical PV GABAergic development remain largely uncharacterized. In both in vivo and in vitro models, we identify here that deletion of the α7 nAChR gene in mice impairs cortical PV GABAergic development and recapitulates many of the characteristic neurochemical deficits in PV-positive GABAergic interneurons found in schizophrenia. α7 nAChR null mice had decreased cortical levels of GABAergic markers including PV, glutamic acid decarboxylase 65/67 (GAD65/67) and the α1 subunit of GABAA receptors, particularly reductions of PV and GAD67 levels in cortical PV-positive interneurons during late postnatal life and adulthood. Cortical GABAergic synaptic deficits were identified in the prefrontal cortex of α7 nAChR null mice and α7 nAChR null cortical cultures. Similar disruptions in development of PV-positive GABAergic interneurons and perisomatic synapses were found in cortical cultures lacking α7 nAChRs. Moreover, NMDA receptor expression was reduced in GABAergic interneurons, implicating NMDA receptor hypofunction in GABAergic deficits in α7 nAChR null mice. Our findings thus demonstrate impaired cortical PV GABAergic development and multiple characteristic neurochemical deficits reminiscent of schizophrenia in cortical PV-positive interneurons in α7 nAChR gene deletion models. This implicates crucial roles of α7 nAChRs in cortical PV GABAergic development and dysfunction in schizophrenia and other neuropsychiatric disorders.
authors.affiliation: Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States; Department of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Lin
authors.affiliation: Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States; Department of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States.
authors.forename: Fu-Chun
authors.initials: FC
authors.lastname: Hsu
authors.affiliation: Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States; Department of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States.
authors.forename: Bailey H
authors.initials: BH
authors.lastname: Baumann
authors.affiliation: Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States; Department of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Coulter
authors.affiliation: Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States; Department of Child Psychiatry, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States.
authors.forename: Stewart A
authors.initials: SA
authors.lastname: Anderson
authors.affiliation: Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States; Department of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States. Electronic address: lynchd@mail.med.upenn.edu.
authors.forename: David R
authors.initials: DR
authors.lastname: Lynch
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D010320:Parvalbumins / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000172:deficiency* / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: C579166:Chrna7 protein, mouse; D010320:Parvalbumins; D011963:Receptors, GABA-A; D064569:alpha7 Nicotinic Acetylcholine Receptor; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2
keywords: Cortex; GABAergic; NMDA receptor; Parvalbumin; α7 nicotinic ACh receptor