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

Michael A. Benneyworth, Alexander S. Roseman, Alo C. Basu, Joseph T. Coyle

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)267-271
Number of pages5
JournalNeuroscience Letters
Volume488
Issue number3
DOIs
StatePublished - Jan 25 2011

Bibliographical note

Funding Information:
This research was supported by NIH Grants MH05129 (JTC) and P50 MH060450 (JTC). We thank Jiamin Feng for genotyping and maintaining our animal colony. We thank Dr. Sabina Berretta and Dr. Harry Pantazopoulos for their assistance with the immunohistochemical studies.

Keywords

  • D-Serine
  • GAD67
  • Ketamine
  • NMDA receptor
  • Parvalbumin
  • Phencyclidine

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