1. ¹Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA
2. ²Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, USA

Correspondence: Dr KM Johnson, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555-1031, USA. Tel: +1 409 772 9623; Fax: +1 409 772 9642; E-mail: kmjohnso@utmb.edu

Received 28 March 2007; Revised 25 May 2007; Accepted 12 June 2007; Published online 18 July 2007.

Abstract

N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) can induce positive and negative symptoms of schizophrenia in humans and related effects in rodents. PCP treatment of developing rats induces apoptotic neurodegeneration and behavioral deficits later in life that mimic some symptoms of schizophrenia. The precise mechanism of PCP-induced neural degeneration is unknown. This study used selective antagonists, siRNA, and Western analysis to investigate the role of the Akt-glycogen synthase kinase-3 (GSK-3) pathway in PCP-induced neuronal apoptosis in both neuronal culture and postnatal day 7 rats. PCP administration in vivo and in vitro reduced the phosphorylation of Akt^Ser427 and GSK-3^Ser9, decreasing Akt activity and increasing GSK-3 activity. The alteration of Akt-GSK-3 signaling parallels the temporal profile of caspase-3 activation by PCP. Reducing GSK-3 activity by application of selective inhibitors or depletion of GSK-3 by siRNA attenuates caspase-3 activity and blocks PCP-induced neurotoxicity. Moreover, increasing synaptic strength by either activation of L-type calcium channels with BAY K8644 or potentiation of synaptic NMDA receptors with either a low concentration of NMDA or bicuculline plus 4-aminopyridine completely blocks PCP-induced cell death by increasing Akt phosphorylation. These neuroprotective effects are associated with activation of phosphoinositide-3-kinase-Akt signaling, and to a lesser extent, the MAPK signaling pathway. Overall, these data suggest that PCP-induced hypofunction of synaptic NMDA receptors impairs the Akt-GSK-3 cascade, which is necessary for neuronal survival during development, and that interference with this cascade by PCP or natural factors may contribute to neural pathologies, perhaps including schizophrenia.