Failure of NMDA receptor hypofunction to induce a pathological reduction in PV-positive GABAergic cell markers

Abstract

Reduction in cortical presynaptic markers, notably parvalbumin (PV), for the chandelier subtype of inhibitory γ-amino-butyric acid (GABA) interneurons is a highly replicated post-mortem finding in schizophrenia. Evidence from genetic and pharmacological studies implicates hypofunction of N-methyl-D-aspartate receptor (NMDAR)-mediated glutamatergic signaling as a critical component of the pathophysiology of schizophrenia. Serine racemase (SR) produces the endogenous NMDAR co-agonist D-serine, and disruption of the SR gene results in reduced NMDAR signaling. SR null mutant (−/−) mice were used to study the link between NMDAR hypofunction and decreased PV expression, assessed by immunoreactive (IR) cell density in the medial prefrontal cortex and hippocampus and protein levels in brain homogenates from the frontal cortex and hippocampus. Contrary to expectations, SR −/− mice showed modest elevations in PV-IR cell density and no difference in PV expression in brain homogenate. To control for these surprising results, we investigated PV expression in mice and rats following subchronic phencyclidine or ketamine treatments in adulthood. PV expression was not affected by drug these treatment in either species, failing to reproduce previously published findings. Our findings challenge the hypothesis that pathological deficits in PV expression are simply a consequence of NMDAR hypofunction.

Comparison of the effects of acute and chronic administration of ketamine on hippocampal oscillations: relevance for the NMDA receptor hypofunction model of schizophrenia

“…Thus, understanding the relationship between the two parameters in this model will require further experiments in a larger number of animals. These will also have to include different time points as PV+ cell loss was still absent 72 hours after the treatment, according to a recent study (Benneyworth et al, 2011), even though theta impairment started to manifest at that early stage in the present study (wk0 in Figs. 4 and 7B).…”

Developmental Age Differentially Mediates the Calcium-Binding Protein Parvalbumin in the Rat: Evidence for a Selective Decrease in Hippocampal Parvalbumin Cell Counts

“…1), which may not account for subthreshold expression. While this method of quantification is well defined and often used [36,38,40,41,43], it should be noted that other methods (e.g. unbiased stereology; Western blot) might provide additional quantitative and qualitative information, which could change the overall interpretation of the findings.…”

“…Specifically, despite using similar NMDA antagonist treatments, there have been conflicting reports of either a decrease [36,37,38,39,40,41], increase [42], no change [43], or mixed/variable findings [44] in PV visualization either via microscopic (e.g. stereology or cell counts [36,38,40,41,43]) and/or protein (e.g. Western blot [43]) analyses.…”

“…stereology or cell counts [36,38,40,41,43]) and/or protein (e.g. Western blot [43]) analyses. These discrepancies are likely due to the inherent differences in baseline PV as a function of age and/or behavioral experience in these subjects, all of which vary between the aforementioned studies, underscoring the need for characterization and anatomical specificity of the number of PV-expressing cells in naïve subjects across postnatal development.…”

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

“…In addition, if GluN2D subunits do contribute to schizophrenia symptoms, then drug-free GluN2D-KO mice may have behavioral defects and reduced PV expression as seen in schizophrenia patients (Lisman et al, 2008) and in rodents after chronic NMDAR blockade (Abekawa et al, 2007;Behrens et al, 2007;Benneyworth et al, 2011). Consequently, we also evaluated spatial learning and PV expression levels in untreated WT and GluN2D-KO mice.…”