The expression of long-term potentiation: reconciling the preists and the postivists

Abstract

Long-term potentiation (LTP) of excitatory synaptic transmission in the hippocampus has been investigated in great detail over the past 40 years. Where and how LTP is actually expressed, however, remain controversial issues. Considerable evidence has been offered to support both pre- and postsynaptic contributions to LTP expression. Though it is widely held that postsynaptic expression mechanisms are the primary contributors to LTP expression, evidence for that conclusion is amenable to alternative explanations. Here, we briefly review some key contributions to the 'locus' debate and describe data that support a dominant role for presynaptic mechanisms. Recognition of the state-dependency of expression mechanisms, and consideration of the consequences of the spatial relationship between postsynaptic glutamate receptors and presynaptic vesicular release sites, lead to a model that may reconcile views from both sides of the synapse.

Keywords: hippocampus; optical quantal analysis; presynaptic; release probability; silent synapse; synaptic plasticity.

Figure 1.

A simplified model of the expression of NMDA-dependent LTP at CA1 associational/commissural synapses. (a,b) Postsynaptic expression mechanisms are responsible for LTP at silent synapses. (a) Transmission fails at silent synapses prevalent in immature CA1, as any postsynaptic AMPARs are too far from the active zone to encounter activating concentrations of released glutamate (shading in synaptic cleft), while NMDARs, though suitably localized, are blocked by Mg²⁺ at normal resting potentials. (b) Following an LTP-inducing stimulus, Ca²⁺ enters the postsynaptic cell and activates CaMKII, mediating extrasynaptic insertion of GluA1-AMPAR/stargazin which then diffuses into the synaptic membrane. Stargazin mediates synaptic trapping of the AMPAR by binding to vacant PSD-95 PDZ1/2 domains (slots) close to the active zone. Additional GluA1-AMPARs inserted at extrasynaptic sites cannot detect glutamate released in the cleft. Synaptic GluA1-AMPARs are subsequently exchanged for GluA2-containing AMPARs. (c) Presynaptic expression mechanisms are responsible for LTP at active synapses. Following an LTP-inducing stimulus, new PSD-95 is added to the edges of the postsynaptic density (PSD), making available new slots for GluA recruitment. GluA1-AMPARs inserted extrasynaptically diffuse laterally to these slots, but are too far from the vesicular fusion site at the presynaptic active zone to be activated by released glutamate. These GluA1-AMPARs can also exchange with GluA2-AMPARs in the PSD closer to the active zone; such exchange can alter rectification properties of synaptic currents, but will have little effect on EPSP amplitude. New GluA1-AMPARs are also recruited to replenish extrasynaptic sites. Surface adhesion molecules (SAMs) recruited to slots in the new synaptic PSD-95 recruit binding partners in the presynaptic membrane, in turn triggering an increase in the probability of neurotransmitter release by mechanisms that may include (i) increased spatial coupling of VGCCs to release machinery, (ii) increased number of docked/primed vesicles and (iii) recruitment of new VGCCs to the presynaptic membrane, as well as increased Ca²⁺ sensitivity of the vesicular release machinery, change from partial to full vesicular fusion, and various other mechanisms not shown.