Differential vulnerability of hippocampal CA3-CA1 synapses to Aβ

Amyloid-beta (A beta) and tau protein are both involved in the pathogenesis of Alzheimer's disease. A beta produces synaptic deficits in wild-type mice that are not seen in Mapt(-/-) mice, suggesting that tau protein is required for these effects of A beta. However, whether some synapses are more selectively affected and what factors may determine synaptic vulnerability to A beta are poorly understood. Here we first observed that burst timing-dependent long-term potentiation (b-LTP) in hippocampal CA3-CA1 synapses, which requires GluN2B subunit-containing NMDA receptors (NMDARs), was inhibited by human A beta(1-42) (hA beta) in wild-type (WT) mice, but not in tau-knockout (Mapt(-/-)) mice. We then tested whether NMDAR currents were affected by hA beta; we found that hA beta reduced the postsynaptic NMDAR current in WT mice but not in Mapt(-/-) mice, while the NMDAR current was reduced to a similar extent by the GluN2B-selective NMDAR antagonist Ro 25-6981. To further investigate a possible difference in GluN2B-containing NMDARs in Mapt(-/-) mice, we used optogenetics to compare NMDAR/AMPAR ratio of EPSCs in CA1 synapses with input from left vs right CA3. It was previously reported in WT mice that hippocampal synapses in CA1 that receive input from the left CA3 display a higher NMDAR charge transfer and a higher Ro-sensitivity than synapses in CA1 that receive input from the right CA3. Here we observed the same pattern in Mapt(-/-) mice, thus differential NMDAR subunit expression does not explain the difference in hA beta effect on LTP. Finally, we asked whether synapses with left vs right CA3 input are differentially affected by hA beta in WT mice. We found that NMDAR current in synapses with input from the left CA3 were reduced while synapses with input from the right CA3 were unaffected by acute hA beta exposure. These results suggest that hippocampal CA3-CA1 synapses with presynaptic axon originating in the left CA3 are selectively vulnerable to A beta and that a genetic knock out of tau protein protects them from A beta synaptotoxicity.

Automated summary

The study shows that both A beta and tau protein play a role in the development of Alzheimer's disease. A beta affects synaptic deficits in wild-type mice, but not in mice without tau protein. Additionally, CA3-CA1 synapses in the hippocampus with presynaptic axons from the left CA3 are more vulnerable to A beta.