PMID- 16641230
OWN - NLM
STAT- MEDLINE
DCOM- 20060523
LR  - 20211027
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 26
IP  - 17
DP  - 2006 Apr 26
TI  - Preconditioning doses of NMDA promote neuroprotection by enhancing neuronal 
      excitability.
PG  - 4509-18
AB  - Neuroprotection can be induced by low doses of NMDA, which activate both synaptic 
      and extrasynaptic NMDA receptors. This is in apparent contradiction with our 
      recent findings that extrasynaptic NMDA receptor signaling exerts a dominant 
      inhibitory effect on prosurvival signaling from synaptic NMDA receptors. Here we 
      report that exposure to low preconditioning doses of NMDA results in preferential 
      activation of synaptic NMDA receptors because of a dramatic increase in action 
      potential firing. Both acute and long-lasting phases of neuroprotection in the 
      face of apoptotic or excitotoxic insults are dependent on this firing 
      enhancement. Key mediators of synaptic NMDA receptor-dependent neuroprotection, 
      phosphatidylinositol 3 kinase-Akt (PI3 kinase-Akt) signaling to Forkhead box 
      subgroup O (FOXO) export and glycogen synthase kinase 3beta (GSK3beta) inhibition 
      and cAMP response element-binding protein-dependent (CREB-dependent) activation 
      of brain-derived neurotrophic factor (BDNF), can be induced only by low doses of 
      NMDA via this action potential-dependent route. In contrast, NMDA doses on the 
      other side of the toxicity threshold do not favor synaptic NMDA receptor 
      activation because they strongly suppress firing rates below baseline. The 
      classic bell-shaped curve depicting neuronal fate in response to NMDA dose can be 
      viewed as the net effect of two antagonizing (synaptic vs extrasynaptic) curves: 
      via increased firing the synaptic signaling dominates at low doses, whereas 
      firing becomes suppressed and extrasynaptic signaling dominates as the toxicity 
      threshold is crossed.
FAU - Soriano, Francesc X
AU  - Soriano FX
AD  - Centre for Neuroscience Research, University of Edinburgh, Edinburgh EH9 1QH, 
      United Kingdom.
FAU - Papadia, Sofia
AU  - Papadia S
FAU - Hofmann, Frank
AU  - Hofmann F
FAU - Hardingham, Neil R
AU  - Hardingham NR
FAU - Bading, Hilmar
AU  - Bading H
FAU - Hardingham, Giles E
AU  - Hardingham GE
LA  - eng
GR  - 078178/WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 6384-92-5 (N-Methylaspartate)
SB  - IM
MH  - Action Potentials/drug effects/*physiology
MH  - Animals
MH  - Apoptosis/drug effects/physiology
MH  - Cell Survival/drug effects/physiology
MH  - Cells, Cultured
MH  - Dose-Response Relationship, Drug
MH  - Hippocampus/drug effects/embryology/*physiology
MH  - N-Methylaspartate/*administration & dosage
MH  - Neurons/drug effects/*physiology
MH  - Neuroprotective Agents/*administration & dosage
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, N-Methyl-D-Aspartate/*metabolism
MH  - Synaptic Transmission/drug effects/*physiology
PMC - PMC2561857
MID - UKMS2467
OID - NLM: UKMS2467
EDAT- 2006/04/28 09:00
MHDA- 2006/05/24 09:00
PMCR- 2006/10/26
CRDT- 2006/04/28 09:00
PHST- 2006/04/28 09:00 [pubmed]
PHST- 2006/05/24 09:00 [medline]
PHST- 2006/04/28 09:00 [entrez]
PHST- 2006/10/26 00:00 [pmc-release]
AID - 26/17/4509 [pii]
AID - 10.1523/JNEUROSCI.0455-06.2006 [doi]
PST - ppublish
SO  - J Neurosci. 2006 Apr 26;26(17):4509-18. doi: 10.1523/JNEUROSCI.0455-06.2006.