Nomadic AMPA Receptors and LTP

What are the broader implications of these two reports? One feature of LTP is its reversibility: once established, application of low-frequency stimulus train can decrease the synaptic strength. When applied to naive synapyses (i.e., in fresh brain slices), such low frequency stimulation induces a long-lasting depression of synaptic responses known as long-term depression (LTD). If AMPA receptor insertion is the mechanism by which LTP is expressed, its reversal might involve removal of AMPA receptors from the dendritic sites. In this case one might expect that LTD would also be impaired in GluR1 knockout mice. Recent work from Malenka and colleagues demonstrates that GluR1 subunits indeed move away from synaptic locations in response to LTD induction protocol in cultured hippocampal neurons (Carroll et al. 1999xCarroll, R.C., Lissin, D.V., Zastrow, M.V., Nicoll, R.A., and Malenka, R.C. Nat. Neurosci. 1999; 2: 454–460Crossref | PubMed | Scopus (342)See all ReferencesCarroll et al. 1999). A decrease in the frequency of spontaneous miniature events indicated a reduction in the number of functional synapses. The bidirectionality of long-term synaptic plasticity may, therefore, be reflected by GluR1 traffic, whose cell surface expression at dendritic spines could be modulated in response to synaptic activity.We have primarily discussed the postsynaptic mechanisms of expression of long-term synaptic plasticity with AMPA receptors playing a key role. Nevertheless, there is direct evidence for potentiation of presynaptic vesicle turnover following LTP induction protocol at synapses formed between dissociated hippocampal neurons grown in culture (11xMalgaroli, A., Ting, A.E., Wendland, B., Bergamaschi, A., Villa, A., Tsien, R.W., and Scheller, R.H. Science. 1995; 268: 1624–1628Crossref | PubMedSee all References, 17xRyan, T.A., Ziv, N.E., and Smith, J.E. Neuron. 1996; 17: 125–134Abstract | Full Text | Full Text PDF | PubMed | Scopus (86)See all References). While it is not clear whether the mechanisms of LTP expression are different between various preparations, a similar approach may be applied to hippocampal slices to directly image synaptic vesicle traffic as a function of LTP induction.An important consequence of LTP is thought to be its conversion to the protein synthesis–dependent phase known as late LTP (L-LTPMilner et al. 1998xMilner, B., Squire, L.R., and Kandel, E.R. Neuron. 1998; 20: 445–468Abstract | Full Text | Full Text PDF | PubMed | Scopus (772)See all ReferencesMilner et al. 1998). The physiological significance of L-LTP has been supported by the fact that L-LTP is reminiscent of memory consolidation in intact organisms, which also display a protein synthesis requirement. What are the implications of a GluR1 insertion-dependent mechanism of LTP for L-LTP induction? The initial enhancement of synaptic strength could be mediated by phosphorylating serine residues on GluR1 that are already present in the postsynaptic density, and hence can be accomplished rapidly. At the same time exocytic delivery of GluR1 could be triggered by Ca2+ during LTP induction. The aftermath of the incorporation and/or changes in the properties of GluR1-containing AMPA receptors could then create a disturbance in the postsynaptic density and may initiate a cascade of events that orchestrates the reorganization of the dendritic cellular cytoskeleton, thereby creating a permanent imprint of LTP.In summary, these studies advance the case for silent synapses in LTP but emphasize that we are still far from identifying the cellular substrate for hippocampal-dependent learning and memory. We continue to struggle with the difficulty in devising a behavioral assay that is solely dependent on the hippocampus without knowing the precise function of the hippocampus in rodents and lacking knowledge of the exact mechanisms underlying LTP in the hippocampus. The answers to these questions would simplify experimental schemes that directly address the functional significance of LTP. The good news is that the solution to the latter problem—cellular and molecular mechanisms of LTP—is making headway. In particular, recent findings illustrate the importance of cell biological approaches. Some of the immediate problems concerning the postsynaptic mechanisms of LTP are the basis for regulating the composition of AMPA receptors at synapses, their differential targeting to the postsynaptic density, and assembly and maintenance of the postsynaptic receptors at the postsynaptic density. Current findings do not rule out a presynaptic contribution to LTP mechanisms; thus, cellular and molecular studies probing presynaptic function also promise to be informative. Optimists as we are, the cell biology of the synapse may provide the final word on the long-standing controversy on the mechanisms of LTP expression.*To whom correspondence should be addressed (e-mail: ygoda@ucsd.edu).