An N-methyl-d-aspartate-receptor dependent, late-phase long-term depression in middle-aged mice identifies no GluN2-subunit bias

Late-phase long-term depression (L-LTD) in middle-aged mice has been difficult to achieve and maintain. Here we report an electrically induced, homosynaptic, input-specific form of LTD that could be stably maintained for at least 4 h in the CA1 area of hippocampal slices of 10-14 months old mice. This form of L-LTD was similar in magnitude in aged, middle-aged and young mice and was blocked by high concentrations of broad-spectrum N-methyl-d-aspartate receptor (NMDAR) antagonists such as d(-)-2-amino-5-phospho-pentanoic acid (d-AP5) and (R)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP). Extracellular and whole cell recordings revealed a decreased sensitivity to d-AP5 with age, without any differences in NMDAR conductance between the age groups tested. This L-LTD could be inhibited neither by common doses of NMDA-subunit specific antagonists like zinc, ifenprodil and Ro-25-6981, nor by various co-applications of these compounds. In addition to the lack of any GluN2 subunit bias, L-LTD did not show any discernible involvement of L-type voltage-gated calcium channels. In conclusion, our results do not support any specific role of NMDAR subunits in LTD.

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