Alzheimer amyloid beta-peptide inhibits the late phase of long-term potentiation through calcineurin-dependent mechanisms in the hippocampal dentate gyrus.
The perforant path projecting from the entorhinal cortex to the hippocampal dentate gyrus is a particularly vulnerable target to the early deposition of amyloid beta (Abeta) peptides in Alzheimer's brain. The authors previously showed that brief applications of Abeta at subneurotoxic concentrations suppressed the early-phase long-term potentiation (E-LTP) in rat dentate gyrus. The current study further examines the effect of Abeta on the late-phase LTP (L-LTP) in this area. Using multiple high-frequency stimulus trains, a stable L-LTP lasting for at least 3 h was induced in the medial perforant path of rat hippocampal slices. Bath application of Abeta(1-42) (0.2-1.0 microM) during the induction trains attenuated both the initial and late stages of L-LTP. On the other hand, Abeta(1-42) perfusion within the first hour following the induction primarily impaired the late stage of L-LTP, which resembled the action of the protein synthesis inhibitor emetine. Blockade of calcineurin activity with FK506 or cyclosporin A completely prevented Abeta-induced L-LTP deficits. These results suggest that Abeta(1-42) impaired both the induction and maintenance phase of dentate L-LTP through calcineurin-dependent mechanisms. In the concentration range effective for inhibiting L-LTP, Abeta(1-42) also reduced the amplitude of NMDA receptor-mediated synaptic currents in dentate granule cells via a postsynaptic mechanism. In addition, concurrent applications of Abeta(1-42) with the protein synthesis inhibitor caused no additive reduction of L-LTP, indicating a common mechanism underlying the action of both. Thus, inhibition of NMDA receptor channels and disruption of protein synthesis were two possible mechanisms contributing to Abeta-induced L-LTP impairment.
Chen
Qi-Sheng
QS
Department of Psychiatry and Biobehavioral Sciences, University of California-Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90024, USA.
Wei
Wei-Zheng
WZ
Shimahara
Takeshi
T
Xie
Cui-Wei
CW
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D016572:Cyclosporine / Q000009:adverse effects; D018891:Dentate Gyrus / Q000378:metabolism*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000009:adverse effects; D017774:Long-Term Potentiation; D008297:Male; D016202:N-Methylaspartate / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000009:adverse effects
D016229:Amyloid beta-Peptides; D007166:Immunosuppressive Agents; D010743:Phospholipids; D016202:N-Methylaspartate; D016572:Cyclosporine; D019703:Calcineurin; D016559:Tacrolimus