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.

GluN2D N-Methyl-D-Aspartate Receptor Subunit Contribution to the Stimulation of Brain Activity and Gamma Oscillations by Ketamine: Implications for Schizophrenia

“…Thus, acute administration of ketamine or phencyclidine (PCP) enhances excitatory activity in corticolimbic structures and increases basal levels of gamma oscillations (Duncan et al, 1999;Duncan et al, 2000;Homayoun and Moghaddam, 2007;Nakazawa et al, 2012;Hunt and Kasicki, 2013;Kocsis et al, 2013). Accordingly, selective reduction of the common GluN1 NMDAR subunit in PV cells, increases basal gamma oscillations, decreases NMDAR antagonist-induced gamma oscillations, and promotes schizophrenia-associated behavioral symptoms (Belforte et al, 2010;Korotkova et al, 2010;Carlen et al, 2012;Billingslea et al, 2014). These effects could also be mediated by PV-containing interneurons in the thalamic reticular nucleus (Frassoni et al, 1991;Llinas et al, 2005).…”

The involvement of <italic>N</italic>-methyl-d-aspartate receptor (NMDAR) subunit NR1 in the pathophysiology of schizophrenia

“…These mice also modeled the deficits of schizophrenia patients in auditory gating in the paired tone paradigm [90,91]. Further studies demonstrated that parvalbumin (PV) interneurons in the NR1 mutants were suggested to be the crucial neuronal populations mediating the sensory gating function involved in the pathophysiology of schizophrenia [79]. Event-related potentials (ERPs) were found to be abnormal in NR1-hypomorphic mice, and thus were used as a paradigm to investigate cognitive processes, such as selective attention [61].…”

Cellular and Circuit Models of Increased Resting State Network Gamma Activity in Schizophrenia

“…Mice with a selective pyramidal cell knock out of NR1 have increased gamma baseline power as measured by EEG (Tatard-Leitman et al, 2015) ( Figure 2). Similarly, mice with a selective knock out of NR1 in a subset of interneurons that express the calcium binding protein parvalbumin (PV) also have a significant increase in baseline EEG gamma power Billingslea et al, 2014). Additionally, animals with a developmental knock out of NR1 in a subset of interneurons (40-50% of cortical interneurons) exhibit a high spontaneous LFP activity in the primary auditory cortex (Nakao and Nakazawa, 2014).…”

“…For example, developmental knockdown of NR1 in a broad range of interneurons causes a decrease in short term memory . However, animals with a selective knock out of NR1 in PV interneurons have reduced working memory in some studies (Korotkova et al, 2010) but significantly improved T-maze performance in others (Billingslea et al, 2014). Thus the role of impaired interneuron function in mediating functional deficits that are associated with increased resting gamma power remains unclear.…”

“…As with cognitive deficits and locomotion, there is a high degree of overlap between increased baseline gamma activity and reduced social interactions. For example, there is a reduction in social behavior in mice with knockout of 1) dysbindin, 2) Erbb4, 3) PV-selective NR1, 4) general interneuron NR1, 5) pyramidal cell-selective NR1 and 6) NR1 hypomorphs Korotkova et al, 2010;Gandal et al, 2012c;Billingslea et al, 2014;Tatard-Leitman et al, 2015). Similarly, rats treated prenatally with MAM and NVHL rats also have social deficits, suggesting that both genetic and developmental lesion models that cause increased baseline gamma power also cause social impairments (Sams-Dodd et al, 1997;O'Donnell, 2011).…”