The Role of Akt-GSK-3β Signaling and Synaptic Strength in Phencyclidine-Induced Neurodegeneration

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-3b (GSK-3b) 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-3b Ser9, decreasing Akt activity and increasing GSK-3b activity. The alteration of Akt-GSK-3b signaling parallels the temporal profile of caspase-3 activation by PCP. Reducing GSK-3b activity by application of selective inhibitors or depletion of GSK-3b 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-3b 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.

Antipsychotic drug mechanisms: links between therapeutic effects, metabolic side effects and the insulin signaling pathway

“…Activating L-type calcium channels (which favors cell survival) or NMDA receptors blocked both PCP-induced neurotoxicity and reduction in phospho-Ser473-Akt. 57 In both cases, adding a specific inhibitor of Akt restored the neurotoxicity of PCP, indicating that the PI3K/Akt pathway was primarily responsible for protecting against the PCP-induced neurotoxicity. 57 As expected, PCP administration also led to decreased phosphoSer9-GSK-3b in rat frontal cortex, hippocampus and striatum, along with in rat neuronal culture and no change in total GSK-3b, indicating increased activity of GSK-3b.…”

“…57 In both cases, adding a specific inhibitor of Akt restored the neurotoxicity of PCP, indicating that the PI3K/Akt pathway was primarily responsible for protecting against the PCP-induced neurotoxicity. 57 As expected, PCP administration also led to decreased phosphoSer9-GSK-3b in rat frontal cortex, hippocampus and striatum, along with in rat neuronal culture and no change in total GSK-3b, indicating increased activity of GSK-3b. 57 Selective inhibition of GSK-3b eliminated the neurotoxic effects of PCP 57 again implicating a role for this pathway in the neurotoxic effects of PCP.…”

“…58 In neuronal culture, PCP can be toxic. 57 In rats, PCP administration led to decreased phospho-Ser473-Akt but stable total Akt in frontal cortex, hippocampus and striatum. 57 Similar results were observed in rat neuronal culture, 57 indicating that PCP leads to decreased activity of Akt.…”

“…57 In rats, PCP administration led to decreased phospho-Ser473-Akt but stable total Akt in frontal cortex, hippocampus and striatum. 57 Similar results were observed in rat neuronal culture, 57 indicating that PCP leads to decreased activity of Akt. Activating L-type calcium channels (which favors cell survival) or NMDA receptors blocked both PCP-induced neurotoxicity and reduction in phospho-Ser473-Akt.…”

“…56 Data from studies on the effects of NMDA receptor antagonists on the insulin signaling pathway also indicate abnormalities of insulin signaling in schizophrenia. 57 Phencyclidine (PCP) or ketamine use can lead to schizophrenia-like symptoms in humans. 58 In neuronal culture, PCP can be toxic.…”