Postnatal Phencyclidine Administration Selectively Reduces Adult Cortical Parvalbumin-Containing Interneurons

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.

Redox Dysregulation Affects the Ventral But Not Dorsal Hippocampus: Impairment of Parvalbumin Neurons, Gamma Oscillations, and Related Behaviors

“…Thus, prenatal immune challenge at E9 affects PV in the PFC, while similar insult at E17 impacts PV in both PFC and VH (Meyer et al, 2008). Likewise, blockade of NMDAR at prenatal, postnatal, adolescent or adult age does not impact PV-IR FSI in the same way and same brain structures (Abekawa et al, 2007;Wang et al, 2008;Zhang et al, 2008). A GSH deficit has also region-and time-specific effects on PV-IR FSI, causing reduction of PV-IR FSI in the VH of adults but affecting also postnatal maturation of PV FSI in the anterior cingulate cortex (Cabungcal et al, 2006;Do et al, 2009a).…”

Schizophrenia-Like Phenotype Inherited by the F2 Generation of a Gestational Disruption Model of Schizophrenia

“…Post-mortem studies on schizophrenia patients report a decreased PV expression in the prefrontal cortex and hippocampus (Beasley et al, 2002;Hashimoto et al, 2003;Knable et al, 2004). In addition, numerous animal models also report region-specific decreases in PV expression (Amitai et al, 2012;Chen et al, 2014;Francois et al, 2009;Jenkins et al, 2010;Lodge et al, 2009a;Penschuck et al, 2006;Wang et al, 2008). Moreover, we have recently demonstrated that a decrease in PV interneuron function is sufficient to augment hippocampal signaling and produce downstream changes in dopamine system function and behavior (Boley et al, 2014;Shah and Lodge, 2013).…”

Electrophysiological Deficits in Schizophrenia: Models and Mechanisms

“…Furthemore, atypical antispsychotics reverse these impairments. These biochemical and behavioral changes phenotipically resemble observations seen in schizophrenia and may serve as a model of the development of schizophrenia (Broberg et al, 2008, Wang et al, 2008. Finally, Dizocilpine (MK801) is frequently used as an animal model of schizophrenia (Fletcher et al, 1989).…”