The role of P2X7 receptors in a rodent PCP-induced schizophrenia model.
P2X7 receptors (P2X7Rs) are ligand-gated ion channels sensitive to extracellular ATP. Here we examined for the first time the role of P2X7R in an animal model of schizophrenia. Using the PCP induced schizophrenia model we show that both genetic deletion and pharmacological inhibition of P2X7Rs alleviate schizophrenia-like behavioral alterations. In P2rx7+/+ mice, PCP induced hyperlocomotion, stereotype behavior, ataxia and social withdrawal. In P2X7 receptor deficient mice (P2rx7-/-), the social interactions were increased, whereas the PCP induced hyperlocomotion and stereotype behavior were alleviated. The selective P2X7 receptor antagonist JNJ-47965567 partly replicated the effect of gene deficiency on PCP-induced behavioral changes and counteracted PCP-induced social withdrawal. We also show that PCP treatment upregulates and increases the functional responsiveness of P2X7Rs in the prefrontal cortex of young adult animals. The amplitude of NMDA evoked currents recorded from layer V pyramidal neurons of cortical slices were slightly decreased by both genetic deletion of P2rx7 and by JNJ-47965567. PCP induced alterations in mRNA expression encoding schizophrenia-related genes, such as NR2A, NR2B, neuregulin 1, NR1 and GABA α1 subunit were absent in the PFC of young adult P2rx7-/- animals. Our findings point to P2X7R as a potential therapeutic target in schizophrenia.
Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences (IEM HAS), H-1450 Budapest, Hungary.|János Szentágothai School of Neurosciences, Semmelweis University School of PhD Studies, Budapest, Hungary.
Bence
B
Koványi
Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences (IEM HAS), H-1450 Budapest, Hungary.
Cecilia
C
Csölle
Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences (IEM HAS), H-1450 Budapest, Hungary.
Stefano
S
Calovi
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, H-1089 Budapest, Hungary.
Adrienn
A
Hanuska
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, H-1089 Budapest, Hungary.
Erzsébet
E
Kató
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, H-1089 Budapest, Hungary.
László
L
Köles
Janssen Research &Development, LLC, Neuroscience TA, San Diego, CA 92121, USA.
Anindya
A
Bhattacharya
Department of Behavioral Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences (IEM HAS), H-1450, Budapest, Hungary.
József
J
Haller
Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences (IEM HAS), H-1450 Budapest, Hungary.
Beáta
B
Sperlágh
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010622:Phencyclidine / Q000009:adverse effects* / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D017966:Pyramidal Cells / Q000378:metabolism* / Q000473:pathology; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism*; D012559:Schizophrenia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
C000590736:JNJ-47965567; D010879:Piperazines; D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7; D009536:Niacinamide; D010622:Phencyclidine