Neural Plast. 2014;2014:584314. doi: 10.1155/2014/584314.

Abeta(1-42) enhances neuronal excitability in the CA1 via NR2B subunit-containing NMDA receptors.

Varga E1, Juhász G1, Bozsó Z1, Penke B1, Fülöp L1, Szegedi V2.
  • 1Department of Medical Chemistry, University of Szeged, Szeged 6726, Hungary.
  • 2Biological Research Center-Biochemistry, Hungarian Academy of Sciences, Temesvari Körút 32, Szeged 6726, Hungary.

 

Abstract

Neuronal hyperexcitability is a phenomenon associated with early Alzheimer’s disease. The underlying mechanism is considered to involve excessive activation of glutamate receptors; however, the exact molecular pathway remains to be determined. Extracellular recording from the CA1 of hippocampal slices is a long-standing standard for a range of studies both in basic research and in neuropharmacology. Evoked field potentials (fEPSPs) are regarded as the input, while spiking rate is regarded as the output of the neuronal network; however, the relationship between these two phenomena is not fully clear. We investigated the relationship between spontaneous spiking and evoked fEPSPs using mouse hippocampal slices. Blocking AMPA receptors (AMPARs) with CNQX abolished fEPSPs, but left firing rate unchanged. NMDA receptor (NMDAR) blockade with MK801 decreased neuronal spiking dose dependently without altering fEPSPs. Activating NMDARs by small concentration of NMDA induced a trend of increased firing. These results suggest that fEPSPs are mediated by synaptic activation of AMPARs, while spontaneous firing is regulated by the activation of extrasynaptic NMDARs. Synaptotoxic Abeta(1-42) increased firing activity without modifying evoked fEPSPs. This hyperexcitation was prevented by ifenprodil, an antagonist of the NR2B NMDARs. Overall, these results suggest that Abeta(1-42) induced neuronal overactivity is not dependent on AMPARs but requires NR2B.

PMID: 25276438

 

 

vs fig1Figure 1: Abeta(1-42) disrupts glutamate recycling at synapses via NR2B-enriched NMDA receptors. Abeta may enhance the ambient glutamate (Glu) level by the inhibition of Glu uptake of astrocytes and neurons through glutamate transporters (EAATs). As a result, Glu concentration increases in the synaptic cleft.

Elevated ambient Glu level may lead to Glu „spillover” from the synapse and subsequent extrasynaptic NR2B subunit-containing NMDA receptor activation. Excessive activation of NR2B-NMDA receptors increases the Ca2+ influx and activates signaling pathways responsible for excitotoxicity, impaired LTP and finally cell death.

Decreasing ambient Glu level may be able to prevent the synaptic plasticity impairment caused by Abeta.

Abbreviations: Abeta (amyloid-beta), NMDA (N-methyl-D-aspartate receptor), Glu (glutamate), and EAATs (excitatory amino-acid glutamate transporters).

 

 

 

 

 

 

 

 

 

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