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Trinchese F, Fa' M, Liu S, Zhang H, Hidalgo A, Schmidt SD, Yamaguchi H, Yoshii N, Mathews PM, Nixon RA, Arancio O. Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease. J Clin Invest. 2008 Aug;118(8):2796-807. PubMed.
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Rosalind Franklin University/The Chicago Medical School
I recommend this paper as a persuasive examination of the normalizing effects of calpain inhibitors on synaptic and learning deficits in PS1/APP mice—but some clarification or further electrophysiological analysis is first needed to characterize the signaling deficits. In particular, I'm referring to increased frequency of mEPSCs (it would also be useful to see the traces) in the PS/APP cultured neurons (Fig 1D), and the normalized mEPSCs measured in glutamate in 1E. Since the baselines are vastly different between the wild-type and APP/PS1, it actually appears that the frequency of mEPSCs maxes out to a similar level across all conditions. There appears to be no increase in the APP/PS1 cells just because they are already releasing transmitter at a high level. Paired pulse facilitation experiments would have been helpful here to further evaluate presynaptic effects; one might expect a reduction in paired pulse facilitation (PPF) in the APP/PS1 cultures under these conditions, which is consistent with increased synaptic strength—which is not observed here. The input/output curves suggest reduced synaptic strength.
The role of calcium in the presynaptic transmitter release dynamics is fundamental, and may affect calpain activation. As an aside, but perhaps noteworthy, is the inclusion of 60 micromolar calcium in the patch pipette used to record postsynaptic events. This concentration is 100 times the normal cytosolic levels in neurons, and I am curious how calpain activity may differ in the APP/PS1 neurons if more physiological levels were used.
Obviously, these are complicated dynamics, but a few extra experiments to characterize the synaptic dynamics would have been very enlightening. Since the role of calpain in the neuropathology is evident, more detailed information is certainly welcomed.
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