The role of Akt-GSK-3β signaling and synaptic strength in phencyclidine-induced neurodegeneration

Gang Lei, Yan Xia, Kenneth M. Johnson

Research output: Contribution to journalArticle

41 Citations (Scopus)

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-3β (GSK-3β) 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 AktSer427 and GSK-3βSer9, decreasing Akt activity and increasing GSK-3β activity. The alteration of Akt-GSK-3β signaling parallels the temporal profile of caspase-3 activation by PCP. Reducing GSK-3β activity by application of selective inhibitors or depletion of GSK-3β 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-3β 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.

Original languageEnglish (US)
Pages (from-to)1343-1353
Number of pages11
JournalNeuropsychopharmacology
Volume33
Issue number6
DOIs
StatePublished - May 2008

Fingerprint

Glycogen Synthase Kinase 3
Phencyclidine
N-Methyl-D-Aspartate Receptors
Schizophrenia
Caspase 3
Small Interfering RNA
Phosphorylation
L-Type Calcium Channels
4-Aminopyridine
1-Phosphatidylinositol 4-Kinase
Bicuculline
Neuroprotective Agents
N-Methylaspartate
Rodentia
Cell Death
Apoptosis
Pathology

Keywords

  • Akt
  • Glycogen synthase kinase-3β
  • Neurotoxicity
  • NMDA receptor
  • Phencyclidine
  • Schizophrenia

ASJC Scopus subject areas

  • Pharmacology

Cite this

The role of Akt-GSK-3β signaling and synaptic strength in phencyclidine-induced neurodegeneration. / Lei, Gang; Xia, Yan; Johnson, Kenneth M.

In: Neuropsychopharmacology, Vol. 33, No. 6, 05.2008, p. 1343-1353.

Research output: Contribution to journalArticle

Lei, Gang ; Xia, Yan ; Johnson, Kenneth M. / The role of Akt-GSK-3β signaling and synaptic strength in phencyclidine-induced neurodegeneration. In: Neuropsychopharmacology. 2008 ; Vol. 33, No. 6. pp. 1343-1353.
@article{12b1e9901b6144efaa004c9bf483fee2,
title = "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-3β (GSK-3β) 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 AktSer427 and GSK-3βSer9, decreasing Akt activity and increasing GSK-3β activity. The alteration of Akt-GSK-3β signaling parallels the temporal profile of caspase-3 activation by PCP. Reducing GSK-3β activity by application of selective inhibitors or depletion of GSK-3β 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-3β 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.",
keywords = "Akt, Glycogen synthase kinase-3β, Neurotoxicity, NMDA receptor, Phencyclidine, Schizophrenia",
author = "Gang Lei and Yan Xia and Johnson, {Kenneth M.}",
year = "2008",
month = "5",
doi = "10.1038/sj.npp.1301511",
language = "English (US)",
volume = "33",
pages = "1343--1353",
journal = "Neuropsychopharmacology",
issn = "0893-133X",
publisher = "Nature Publishing Group",
number = "6",

}

TY - JOUR

T1 - The role of Akt-GSK-3β signaling and synaptic strength in phencyclidine-induced neurodegeneration

AU - Lei, Gang

AU - Xia, Yan

AU - Johnson, Kenneth M.

PY - 2008/5

Y1 - 2008/5

N2 - 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-3β (GSK-3β) 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 AktSer427 and GSK-3βSer9, decreasing Akt activity and increasing GSK-3β activity. The alteration of Akt-GSK-3β signaling parallels the temporal profile of caspase-3 activation by PCP. Reducing GSK-3β activity by application of selective inhibitors or depletion of GSK-3β 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-3β 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.

AB - 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-3β (GSK-3β) 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 AktSer427 and GSK-3βSer9, decreasing Akt activity and increasing GSK-3β activity. The alteration of Akt-GSK-3β signaling parallels the temporal profile of caspase-3 activation by PCP. Reducing GSK-3β activity by application of selective inhibitors or depletion of GSK-3β 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-3β 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.

KW - Akt

KW - Glycogen synthase kinase-3β

KW - Neurotoxicity

KW - NMDA receptor

KW - Phencyclidine

KW - Schizophrenia

UR - http://www.scopus.com/inward/record.url?scp=42049091873&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=42049091873&partnerID=8YFLogxK

U2 - 10.1038/sj.npp.1301511

DO - 10.1038/sj.npp.1301511

M3 - Article

VL - 33

SP - 1343

EP - 1353

JO - Neuropsychopharmacology

JF - Neuropsychopharmacology

SN - 0893-133X

IS - 6

ER -