Abstract
Transient postnatal NMDA receptor blockade by phencyclidine (PCP), ketamine, or MK-801 induces developmental neuroapoptosis and adult behavioral deficits, which resemble abnormal human behaviors typically present in schizophrenia. This study tested the hypothesis that PCP-induced developmental apoptosis causes a specific deficit of GABAergic interneurons containing parvalbumin (PV), calretinin (CR), or calbindin (CB). Young adult (PND56) rats that were given a single dose of PCP (10 mg/kg) on PND7 exhibited no densitometric change of either CR or CB neurons in any brain region studied, but demonstrated a selective deficit of PV-containing neurons in the superficial layers (II–IV) of the primary somatosensory (S1), motor (M), and retrosplenial cortices, but not in the striatum (CPu) or hippocampus. Further, CR and CB neurons, which were expressed at the time of PCP administration, showed no colocalization with cellular markers of apoptosis (terminal dUTP nick-end labeling (TUNEL) of broken DNA or cleaved caspase-3), indicating that CR- and CB-containing neurons were protected from the toxic effect of PCP and survived into adulthood. This suggests that the deletion of PV neurons occurred during development, but cleaved caspase-3 showed no colocalization with BrdU, a specific marker of S-phase proliferation. These data suggest that the loss of PV-containing neurons was not due to an effect of PCP on proliferating neurons, but rather an effect on post-mitotic neurons. The developmental dependence and neuronal specificity of this effect of PCP provides further evidence that this model may be valuable in exploring the pathophysiology of schizophrenia.
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Acknowledgements
We are grateful to Ms Tiffany E Springsted and Ms Jing Wang for their technical assistance and to Mr Eugene Knutson and Dr Thomas Albrecht, Infectious Disease and Toxicology Optical Imaging Core (IDTOIC), the University of Texas Medical Branch at Galveston, TX, USA for their help with confocal microscopy. This work was supported by grants MH63871 and DA02073 from the US Department of Health and Human Services.
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Wang, C., Yang, S., Xia, Y. et al. Postnatal Phencyclidine Administration Selectively Reduces Adult Cortical Parvalbumin-Containing Interneurons. Neuropsychopharmacol 33, 2442–2455 (2008). https://doi.org/10.1038/sj.npp.1301647
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