Abstract
Excessive stimulation of glutamate receptors is believed to contribute substantially in determining neuronal vulnerability to ischemia. However, how this pathological event predisposes neurons to excitotoxic insults is still largely unknown. By using electrophysiological recordings from single striatal neurons, we demonstrate in a corticostriatal brain-slice preparation that in vitro ischemia (glucose and oxygen deprivation) activates a complex chain of intracellular events responsible for a dramatic and irreversible increase in the sensitivity of striatal neurons to synaptically released glutamate. This process follows the stimulation of bothN-methyl-d-aspartate and metabotropic glutamate receptors and involves the activation of the mitogen-activated protein kinase ERK via protein kinase C. This pathological form of synaptic plasticity might play a role in the cell type-specific neuronal vulnerability in the striatum, because it is selectively expressed in neuronal subtypes that are highly sensitive to both acute and chronic disorders involving this brain area.
Footnotes
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This study was supported by a Telethon (E.729) Grant and a Consiglio Nazionale delle Ricerche (CNR) (Invecchiamento) Grant to P.C. The study was also supported by a Ministero dell'Università e della Ricerca Scientifica e Tecnologica (MURST)/CNR (legge 95/95) Grant and a MURST/Cofinanziamento (1998) Grant to G.B., as well as the Biomed 2 program (to R.A.H. and P.C.) and the French Association pour la Recherche sur le Cancer (R.A.H.).
- Abbreviations:
- LTP
- long-term potentiation
- i-LTP
- ischemic long-term potentiation
- AMPA
- α-amino-3-hydroxy-5-methylisoxazole-4-propionate
- NMDA
- N-methyl-d-aspartate
- mGluR1
- metabotropic glutamate receptor subtype 1
- PKC
- protein kinase C
- MAP
- mitogen-activated protein
- ERK
- extracellular signal receptor-activated kinase
- EPSP
- excitatory postsynaptic potential
- BAPTA
- 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid
- EPSC
- excitatory postsynaptic current
- APV
- 2-amino-5-phosphonovalerate
- MPEP
- 2-methyl-6-(phenylethynyl)-pyridine
- AIDA
- (R,S)-1-aminoindan-1,5-dicarboxylic acid
- LA
- large aspiny
- CNQX
- 6-cyano-2,3-dihydroxy-7-nitroquinoxaline
- RMP
- resting membrane potential
- MEK
- mitogen-activated protein kinase kinase
- Received March 31, 2001.
- Accepted June 21, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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