Parvalbumin cell ablation of NMDA-R1 causes increased resting network excitability with associated social and self-care deficits

Eddie N. Billingslea, Valerie M. Tatard-Leitman, Jaynie Anguiano, Catherine R. Jutzeler, Jimmy Suh, John A. Saunders, Susumu Morita, Robert E. Featherstone, Pavel I. Ortinski, Michael J. Gandal, Robert Lin, Yuling Liang, Raquel E. Gur, Gregory C. Carlson, Chang Gyu Hahn, Steven J. Siegel

Research output: Contribution to journalArticlepeer-review

90 Scopus citations


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.

Original languageEnglish
Pages (from-to)1603-1613
Number of pages11
Issue number7
StatePublished - Jun 2014

Bibliographical note

Funding Information:
Funding was provided by 5R01DA023210-04 (Siegel), 5R01MH074672 -04 (SJ Siegel), 1P50MH096891-01 (RE Gur), T32MH019112 to RE (Gur), as well as Developmental funds from the University of Pennsylvania (SJ Siegel).

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health


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