title: Parvalbumin cell ablation of NMDA-R1 causes increased resting network excitability with associated social and self-care deficits.
abstract: NMDA-receptor (NMDAR) hypofunction is strongly implicated in the pathophysiology of schizophrenia. Several convergent lines of evidence suggest that net excitation propagated by impaired NMDAR signaling on GABAergic interneurons may be of particular interest in mediating several aspects of schizophrenia. However, it is unclear which behavioral domains are governed by a net increase of excitation and whether modulating downstream GABAergic signaling can reverse neural and thus behavioral deficits. The current study determines the selective contributions of NMDAR dysfunction on PV-containing interneurons to electrophysiological, cognitive, and negative-symptom-related behavioral phenotypes of schizophrenia using mice with a PVcre-NR1flox-driven ablation of NR1 on PV-containing interneurons. In addition, we assessed the efficacy of one agent that directly modulates GABAergic signaling (baclofen) and one agent that indirectly modifies NMDAR-mediated signaling through antagonism of mGluR5 receptors (2-methyl-6-(phenylethynyl) pyridine (MPEP)). The data indicate that loss of NMDAR function on PV interneurons impairs self-care and sociability while increasing N1 latency and baseline gamma power, and reducing induction and maintenance of long-term potentiation. Baclofen normalized baseline gamma power without corresponding effects on behavior. MPEP further increased N1 latency and reduced social behavior in PVcre/NR1+/+ mice. These two indices were negatively correlated before and following MPEP such that as N1 latency increases, sociability decreases. This finding suggests a predictive role for N1 latency with respect to social function. Although previous data suggest that MPEP may be beneficial for core features of autism spectrum disorders, current data suggest that such effects require intact function of NMDAR on PV interneurons.
authors: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors: Eddie N
authors: EN
authors: Billingslea
authors: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors: Valerie M
authors: VM
authors: Tatard-Leitman
authors: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors: Jaynie
authors: J
authors: Anguiano
authors: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors: Catherine R
authors: CR
authors: Jutzeler
authors: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors: Jimmy
authors: J
authors: Suh
authors: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors: John A
authors: JA
authors: Saunders
authors: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors: Susumu
authors: S
authors: Morita
authors: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors: Robert E
authors: RE
authors: Featherstone
authors: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors: Pavel I
authors: PI
authors: Ortinski
authors: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors: Michael J
authors: MJ
authors: Gandal
authors: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors: Robert
authors: R
authors: Lin
authors: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors: Yuling
authors: Y
authors: Liang
authors: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors: Raquel E
authors: RE
authors: Gur
authors: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors: Gregory C
authors: GC
authors: Carlson
authors: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors: Chang-Gyu
authors: CG
authors: Hahn
authors: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors: Steven J
authors: SJ
authors: Siegel
mesh_terms: D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001921:Brain / Q000473:pathology*; D004195:Disease Models, Animal; D005071:Evoked Potentials / Q000187:drug effects / Q000235:genetics; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000502:physiology; D018755:GABA Agonists / Q000494:pharmacology; D007398:Interpersonal Relations; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010320:Parvalbumins / Q000172:deficiency* / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D012146:Rest; D012648:Self Care; D012920:Social Behavior Disorders / Q000235:genetics / Q000473:pathology*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; C121673:Gprin1 protein, mouse; D009419:Nerve Tissue Proteins; D010320:Parvalbumins; D011725:Pyridines; D016194:Receptors, N-Methyl-D-Aspartate; C121465:6-methyl-2-(phenylethynyl)pyridine; D001418:Baclofen