Expression of NMDA receptor-dependent LTP in the hippocampus: bridging the divide

Abstract

A consensus has famously yet to emerge on the locus and mechanisms underlying the expression of the canonical NMDA receptor-dependent form of LTP. An objective assessment of the evidence leads us to conclude that both presynaptic and postsynaptic expression mechanisms contribute to this type of synaptic plasticity.

Figure 1

Potential expression mechanisms for LTP. A. LTP could involve presynaptic mechanims due to an increase in p(r), number of release sites (n) or cleft glutamate (glu) concentration. B. Postsynaptic mechanisms could involve a modification of AMPA receptor properties, such as an increase in their mean open-time, probability of opening on binding glutamate p(o), or an increase in their single channel conductance (γ). C. Postsynaptic mechanisms could also involve an increase in the number of AMPA receptors at synapses. D. Synaptic growth is likely to involve both pre and postsynaptic changes.

Figure 2

Evidence for presynaptic changes in LTP. When a single fiber is stimulated, a change in success rate without change in potency establishes that the alteration is presynaptically mediated. (A) A plot of paired-pulse potency (mean amplitude excluding failures) ratio during baseline and following the induction of LTP for 8 neurons. (B) A plot of paired-pulse ratio (mean amplitude including failures) during baseline and following the induction of LTP for the same neurons. Note that despite large PPF during baseline and, for some neurons, following the induction of LTP the paired-pulse potency ratio is approximately 1 both during baseline and following the induction of LTP. (C) A plot of success rate change vs amplitude change for LTP of these neurons. (D) The corresponding plot for potency. Note that for all neurons the increase in EPSC amplitude can be explained by the success rate change and that potency is unaltered. From [25].

Figure 3

Evidence for presynaptic changes in LTP. A. Recordings of excitatory postsynaptic Ca²⁺ transients (EPSCaTs, upper panels) in an activated spine, and simultaneously recorded somatic EPSPs (lower panels) from a neuron in which the imaged spine was the only one contributing to the synaptic response. LTP was associated with a large increase in p(r) with no change in quantal size. Red dots represent successes and black dots failures. B. Images of the spine at rest and during a response. C. Increase in p(r) without increase in potency for three neurons that fulfilled the criteria for a single activated synapse. From [30].

Figure 4

A mechanism for postsynaptic AMPA receptor trafficking in LTP. A. A scheme showing that NMDA receptor activation leads to the activation of PKMζ which stabilizes AMPA receptors at the synapse by promoting the interaction between the GluA2 subunit and N-ethylmaleimide-sensitive factor (NSF). B. ZIP, a peptide that inhibits the activity of PKMζ, inhibits the expression of LTP many hours after its induction. From [85]. C. Pep2m, a peptide that blocks the GluA2-NSF interaction, also inhibits the expression of LTP. From [83].

Figure 5

Multiple mechanisms of expression of LTP. A. Early in development synapses may acquire NMDA receptors before AMPA receptors (so-called silent synapses). B. The unsilencing of silent synapses is likely to involve the synaptic insertion of AMPA receptors. C. Complementary evidence exists showing that functional synapses can increase their synaptic strength via an increase in p(r) PPP = paired-pulse potency. D. There is also evidence for an increase in the quantal size due to the synaptic insertion of AMPA receptors exhibiting, paradoxically, lower γ. E, F. Increases in quantal size, due to an increase in γ (E) or in the number of AMPA receptors (F) have also also been observed.