Two Loci of Expression for Long-Term Depression at Hippocampal Mossy Fiber-Interneuron Synapses

Abstract

Two distinct forms of long-term depression (LTD) exist at mossy fiber synapses between dentate gyrus granule cells and hippocampal CA3 stratum lucidum interneurons. Although induction of each form of LTD requires an elevation of postsynaptic intracellular Ca2+, at Ca2+-impermeable AMPA receptor (CI-AMPAR) synapses, induction is NMDA receptor (NMDAR) dependent, whereas LTD at Ca2+-permeable AMPA receptor (CP-AMPAR) synapses is NMDAR independent. However, the expression locus of either form of LTD is not known. Using a number of criteria, including the coefficient of variation, paired-pulse ratio, AMPA-NMDA receptor activity, and the low-affinity AMPAR antagonist γ-d-glutamyl-glycine, we demonstrate that LTD expression at CP-AMPAR synapses is presynaptic and results from reduced transmitter release, whereas LTD expression at CI-AMPAR synapses is postsynaptic. TheN-ethylmaleimide-sensitive fusion protein-AP2-clathrin adaptor protein 2 inhibitory peptide pep2m occluded LTD expression at CI-AMPAR synapses but not at CP-AMPAR synapses, confirming that CI-AMPAR LTD involves postsynaptic AMPAR trafficking. Thus, mossy fiber innervation of CA3 stratum lucidum interneurons occurs via two parallel systems targeted to either Ca2+-permeable or Ca2+-impermeable AMPA receptors, each with a distinct expression locus for long-term synaptic plasticity.

Chapter 13 Differential mechanisms of transmission and plasticity at mossy fiber synapses

“…Moreover, parameters consistent with changes in presynaptic transmitter release, paired pulse ratio, coefficient of variance (CV), failure rate, and the magnitude of block by the low-affinity glutamate receptor antagonist γ-DGG were all unchanged after LTD of CI-AMPA receptormediated transmission. In addition, this form of LTD relies on an AP-2 dependent internalization of AMPAR by a mechanism similar to that seen at other synapses expressing NMDAR-dependent LTD (Lei et al, 2004).At mossy fiber CP-AMPAR-interneuron synapses, LTD is NMDAR-independent. Moreover, this form of depression is accompanied by changes in the paired pulse ratio, failure rate, and the CV, all indices consistent with changes in presynaptic transmitter release probability.…”

“…Independent support of this presynaptic locus of expression came from experiments using postsynaptic delivery of peptides (pep2m) designed to interfere with AMPA receptor internalization. In contrast to CI-AMPARs, infusion of pep2m into the postsynaptic compartment had no effect of either basal synaptic transmission or the ability to induce LTD at CP-AMPAR synapses (Lei and McBain, 2004).Taken together these data highlight two important aspects of mossy fiber transmission onto inhibitory interneurons. First, mossy fiber-interneuron synapses are constructed from two distinct types of postsynaptic glutamate receptor, GluR2-lacking CP-AMPA receptors and GluR2-containing, CI AMPA receptors.…”

“…Although the induction locus was postsynaptic in both cases, and blocked by inclusion of BAPTA in the recording pipette, the locus of LTD expression was presynaptic at CP-AMPAR but postsynaptic at CI-AMPARs (Figs. 4 and 5) (Lei and McBain, 2004). Importantly the mechanisms underlying either form of LTD were also distinct.…”

“…However, none of these parameters by themselves definitively prove a presynaptic locus. To explore the presynaptic locus of LTD at CP-AMPAR synapses in more detail, Lei and McBain (2004) took advantage of the low-affinity glutamate receptor antagonist γ-DGG. This compound has been used at a number of synapses to probe for changes in the transmitter release profile under a variety of conditions (Liu et al, 1999;Wadiche and Jahr, 2001).…”

“…Interestingly, in synapses that contain a mixture of either CP-AMPARs and CI-AMPARs, i.e. cells with only mild sensitivity to philanthotoxin or are weakly rectifying, it appears that LTD defaults to the presynaptic mechanism (Lei and McBain, 2004).Before discussing this presynaptic form of LTD in greater detail, it is worthwhile pausing to emphasize that these data suggest that a common non-associative induction paradigm triggers a presynaptic form of strengthening at mossy fiber bouton synapses onto pyramidal cells yet simultaneously triggers a long-lasting depression at filopodial synapses onto inhibitory interneurons. This observation strengthens the hypothesis that the anatomical arrangement of filopodia emerging from the parent mossy fiber bouton may serve to function as a solution for a compartmentalization of a biochemical mechanism (for further discussion, see Pelkey and McBain, 2007).…”