MicroRNA-134-5p inhibition rescues long-term plasticity and synaptic tagging/capture in an Aβ(1-42)-induced model of Alzheimer's disease

Baby et al., Aging Cell, 2020, asked whether a single microRNA is enough to account for the loss of synaptic plasticity in an amyloid beta model, and whether blocking it puts the plasticity back. Acute hippocampal slices from adult male Wistar rats were exposed to amyloid beta oligomers, which abolished late long-term potentiation and abolished synaptic tagging and capture, the associative property that lets a weakly stimulated synapse borrow proteins from a strongly stimulated one. Quantitative PCR showed miR-134-5p up 3.5 fold in the injured tissue.

The tool was an AUMantagomir sdASO against miR-134-5p from AUM BioTech, with a matched scrambled control. Four designs were tested and the best gave 80% knockdown at 1 μM. Delivery was bath application into the perfusing artificial cerebrospinal fluid for 3 hours before recording, with no transfection reagent named anywhere in the paper, and the authors put the speed of the effect down to direct uptake by the neurons in the slice. Higher concentrations, 5 μM and 2.5 μM, destabilised the recording baseline, which is why 1 μM was chosen.

With the microRNA inhibited, late potentiation lasted the full 4 hour recording in injured slices and synaptic tagging and capture came back, with significance in both synaptic inputs. The scrambled control did neither. CREB-1 and BDNF, both messenger RNA and protein, rose alongside, giving the electrophysiology a molecular route. Two controls make the result harder to argue with. The rescue depended on new protein synthesis and on the NMDA receptor, and it added no potentiation in healthy slices, so it is a repair of an injured system rather than a general boost. Four of those results were then repeated in slices from aged mice: the rise in the microRNA, the knockdown, the CREB-1 and BDNF messenger RNA rise, and the potentiation rescue. Synaptic tagging and capture was not tested in the mouse and stands in the rat alone, and that section carries no protein blot.