Misplaced NMDA receptors in epileptogenesis contribute to excitotoxicity

Angelisa Frasca, Marlien Aalbers, Federica Frigerio, Fabio Fiordaliso, Monica Salio, Marco Gobbi, Alfredo Cagnotto, Fabrizio Gardoni, Giorgio S. Battaglia, Govert Hoogland, Monica Di Luca, Annamaria Vezzani

Research output: Contribution to journalArticle

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Abstract

Pharmacological blockade of NR2B-containing N-methyl-. d-aspartate receptors (NMDARs) during epileptogenesis reduces neurodegeneration provoked in the rodent hippocampus by status epilepticus. The functional consequences of NMDAR activation are crucially influenced by their synaptic vs extrasynaptic localization, and both NMDAR function and localization are dependent on the presence of the NR2B subunit and its phosphorylation state.We investigated whether changes in NR2B subunit phosphorylation, and alterations in its neuronal membrane localization and cellular expression occur during epileptogenesis, and if these changes are involved in neuronal cell loss. We also explored NR2B subunit changes both in the acute phase of status epilepticus and in the chronic phase of spontaneous seizures which encompass the epileptogenesis phase.Levels of Tyr1472 phosphorylated NR2B subunit decreased in the post-synaptic membranes from rat hippocampus during epileptogenesis induced by electrical status epilepticus. This effect was concomitant with a reduced interaction between NR2B and post-synaptic density (PSD)-95 protein, and was associated with decreased CREB phosphorylation. This evidence suggests an extra-synaptic localization of NR2B subunit in epileptogenesis. Accordingly, electron microscopy showed increased NR2B both in extra-synaptic and pre-synaptic neuronal compartments, and a concomitant decrease of this subunit in PSD, thus indicating a shift in NR2B membrane localization. De novo expression of NR2B in activated astrocytes was also found in epileptogenesis indicating ectopic receptor expression in glia. The NR2B phosphorylation changes detected at completion of status epilepticus, and interictally in the chronic phase of spontaneous seizures, are predictive of receptor translocation from synaptic to extrasynaptic sites.Pharmacological blockade of NR2B-containing NMDARs by ifenprodil administration during epileptogenesis significantly reduced pyramidal cell loss in the hippocampus, showing that the observed post-translational and cellular changes of NR2B subunit contribute to excitotoxicity. Therefore, pharmacological targeting of misplaced NR2B-containing NMDARs, or prevention of these NMDAR changes, should be considered to block excitotoxicity which develops after various pro-epileptogenic brain injuries.

Original languageEnglish
Pages (from-to)507-515
Number of pages9
JournalNeurobiology of Disease
Volume43
Issue number2
DOIs
Publication statusPublished - Aug 2011

Fingerprint

Status Epilepticus
N-Methyl-D-Aspartate Receptors
Phosphorylation
Post-Synaptic Density
Hippocampus
Pharmacology
Seizures
Synaptic Membranes
Neurotransmitter Receptor
Membranes
Pyramidal Cells
Neuroglia
Astrocytes
Brain Injuries
Rodentia
Electron Microscopy
Proteins

Keywords

  • Astroglia
  • Epilepsy
  • Glutamate receptor
  • Neuroprotective agents
  • Seizure

ASJC Scopus subject areas

  • Neurology

Cite this

Misplaced NMDA receptors in epileptogenesis contribute to excitotoxicity. / Frasca, Angelisa; Aalbers, Marlien; Frigerio, Federica; Fiordaliso, Fabio; Salio, Monica; Gobbi, Marco; Cagnotto, Alfredo; Gardoni, Fabrizio; Battaglia, Giorgio S.; Hoogland, Govert; Di Luca, Monica; Vezzani, Annamaria.

In: Neurobiology of Disease, Vol. 43, No. 2, 08.2011, p. 507-515.

Research output: Contribution to journalArticle

Frasca, A, Aalbers, M, Frigerio, F, Fiordaliso, F, Salio, M, Gobbi, M, Cagnotto, A, Gardoni, F, Battaglia, GS, Hoogland, G, Di Luca, M & Vezzani, A 2011, 'Misplaced NMDA receptors in epileptogenesis contribute to excitotoxicity', Neurobiology of Disease, vol. 43, no. 2, pp. 507-515. https://doi.org/10.1016/j.nbd.2011.04.024
Frasca, Angelisa ; Aalbers, Marlien ; Frigerio, Federica ; Fiordaliso, Fabio ; Salio, Monica ; Gobbi, Marco ; Cagnotto, Alfredo ; Gardoni, Fabrizio ; Battaglia, Giorgio S. ; Hoogland, Govert ; Di Luca, Monica ; Vezzani, Annamaria. / Misplaced NMDA receptors in epileptogenesis contribute to excitotoxicity. In: Neurobiology of Disease. 2011 ; Vol. 43, No. 2. pp. 507-515.
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