. Acid-sensing ion channel 1a is a postsynaptic proton receptor that affects the density of dendritic spines. Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16556-61. PubMed.

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  1. I think that this study is very interesting and well carried out. To some extent, this is an exciting new idea that could have a significant impact on the understanding of neurotransmission. It is clearly comparable to the exciting breakthroughs of the 1970s when it was discovered that Ca++ ions, extreme intracellular toxins, played significant intracellular roles. One of the thoughts at that time was that the dendritic spines' role was to allow for control of the Ca++ ions entering the cells during neurotransmission. The same may be thought now for the H+ ion. An interesting aside is that the H+ ion series (it may be in the lyotropic series, which includes Li+, K+, and Na+) was studied most interestingly by Diamond and Wright in the 1960s (that is Jared Diamond, author of Guns, Germs, and Steel).

    I also noted that ASIC1a transgenic mice had increased fear conditioning (reference 25). If I am not mistaken, this was one of the findings of the BACE knockout mice, suggesting an interaction that might be relevant to Alzheimer disease, but in the opposite direction. This relationship is very important for understanding exactly what neuroplastic events are involved with the Alzheimer process.

    I would like to make one comment about the potential relationship of these
    findings to Alzheimer disease:

    • Increased synaptic activity leads to increased acidity.

    • Increased acidity leads to increased synaptic spine structures (this will require increased production of APP and phosphorylation of tau).
    • Increased APP processing and phosphotau will increase likelihood of AD changes (possible increases in Aβ and neuropil thread production in vulnerable subjects, ApoE4 carriers, etc.).
    • Increased AD pathology will cause breaks of neurites leading to loss of synapses, which in turn will put more stress on remaining synapses.
    • Increased synaptic activity at remaining synapses will cause even further increases in acidity, thus setting up a vicious cycle leading downhill to AD in vulnerable cases.

    I believe that this potential cycle has to be considered in the development of Alzheimer disease, and clearly the relationship to acidity is of interest, but not necessarily different from any other factor that can stimulate new synapses—Ca++ ions, any overactivity. The acidity is just one of the stimuli, not yet clearly the critical link.