Repetition of mGluR-dependent LTD causes slowly developing persistent reduction in synaptic strength accompanied by synapse elimination

Synaptic plasticity, the cellular basis of memory, operates in a bidirectional manner. LTP (long-term potentiation) is followed by structural changes that may lead to the formation of new synapses. However, little is known whether LTD (long-term depression) is followed by morphological changes. Here we show that the repetitive induction of metabotropic glutamate receptor (mGluR)-dependent LTD in stable cultures of rat hippocampal slices led to a slowly developing persistent (ranging over weeks) reduction in synaptic strength that was accompanied by the loss of synaptic structures. LTD was induced pharmacologically 1–3 times at 24-h intervals by applying aseptically ACPD (1-aminocyclopentane-1,3-dicarboxylic acid), an agonist of group I/II mGluR, and APV (2-amino-5-phosphonovalerate), an antagonist of the NMDA ( N-methyl- d-aspartate) receptor. One ACPD/APV application induced LTD that lasted less than 24 h. After three LTD inductions, however, a gradual attenuation of the fEPSP (field excitatory postsynaptic potential) amplitude and a decrease in the number of pre- and postsynaptic structures were observed. The blockade of LTD by an mGluR antagonist or a protein phosphatase 2B inhibitor abolished the development of the synaptic attenuation. In contrast to our previous finding that the repetitive LTP induction triggered a slowly developing persistent synaptic enhancement, the incremental and decremental forms of synaptic plasticity appeared to occur symmetrically not only on the minutes–hours time order but also on the days–weeks time order.