Parvalbumin Cell Ablation of NMDA-R1 Causes Increased Resting Network Excitability with Associated Social and Self-Care Deficits.

Neuropsychopharmacology

PubMedID: 24525709

Billingslea EN, Tatard-Leitman VM, Anguiano J, Jutzeler CR, Suh J, Saunders JA, Morita S, Featherstone RE, Ortinski PI, Gandal MJ, Lin R, Liang Y, Gur RE, Carlson GC, Hahn CG, Siegel SJ. Parvalbumin Cell Ablation of NMDA-R1 Causes Increased Resting Network Excitability with Associated Social and Self-Care Deficits. Neuropsychopharmacology. 2014;.
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. Additionally, 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). 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 prior to 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 suggests that MPEP may be beneficial for core features of Autism Spectrum Disorders, current data suggest such effects require intact function of NMDAR on PV-interneurons.Neuropsychopharmacology accepted article preview online, 14 February 2014; doi:10.1038/npp.2014.7.