Presynaptic long-term plasticity

Abstract

Long-term synaptic plasticity is a major cellular substrate for learning, memory, and behavioral adaptation. Although early examples of long-term synaptic plasticity described a mechanism by which postsynaptic signal transduction was potentiated, it is now apparent that there is a vast array of mechanisms for long-term synaptic plasticity that involve modifications to either or both the presynaptic terminal and postsynaptic site. In this article, we discuss current and evolving approaches to identify presynaptic mechanisms as well as discuss their limitations. We next provide examples of the diverse circuits in which presynaptic forms of long-term synaptic plasticity have been described and discuss the potential contribution this form of plasticity might add to circuit function. Finally, we examine the present evidence for the molecular pathways and cellular events underlying presynaptic long-term synaptic plasticity.

Keywords: long-term depression; long-term potentiation; neurotransmitter release; presynaptic plasticity; synaptic plasticity; synaptic vesicle.

Figure 1

Induction mechanisms identified for presynaptic LTP and LTD. (A,B) presynaptic plasticity induced presynaptically (e.g., mossy fiber LTP and LTD). (C) eCB-dependent homosynaptic and heterosynaptic LTD. (D) NO-dependent LTD at excitatory synapses and LTP at inhibitory synapses. (E) postsynaptically induced LTP with as yet unidentified retrograde signaling mechanism (e.g., CA3-CA1 LTP). (F) presynaptic NMDAR-dependent homosynaptic and heterosynaptic LTP (e.g., LTP at cortico-LA synapses). (G) presynaptic LTP gated by mGluR7b at mossy fiber-SLIN synapses. (H) presynaptic LTP gated by CB1R (e.g., LTP at thalamic-LA synapses). AC, adenylate cyclase; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; VGCC, voltage-gated calcium channel; KAR, kainate receptor; mGluR, metabotropic glutamate receptor; eCB, endocannabinoid; CB1R, cannabinoid receptor type 1; NO, nitric oxide; NOS, nitric oxide synthase; CP-AMPAR SLIN, calcium permeable-AMPA receptor containing stratum lucidum interneurons.

Figure 2

Working models of expression mechanisms for presynaptic LTP and LTD. In this schematic, presynaptic molecules implicated in the expression of changes in presynaptic release probability associated with LTP and LTD are shown. In LTP at mossy fiber synapses, the specific interaction of RIM1a with Munc13-1 that promotes activation of Munc13 for vesicle priming is required, indicating that a likely cellular mechanism for increasing release probability may be through changes in the number of primed vesicles (indicated by vesicles adjacent to the terminal membrane). In LTD at hippocampal mossy fiber—stratum lucidum interneuron synapses and the nucleus accumbens, inhibition of P/Q type voltage-gated calcium channel (VGCC) activity is associated with expression of LTD. Whether this modulation of channel activity requires interaction with RIM1a has not been tested. At other synapses, a requirement for Rab3 and RIM1a for LTD has been described. Therefore, in the LTD working model, we also hypothesize that LTD mechanisms opposite to LTP may occur and thus show fewer primed vesicles to lead to a decrease in release probability. However, a requirement for Munc13 in LTD has not yet been tested. In addition, while Rab3a and RIM1a are both implicated in LTP and LTD, whether their interaction is required has also not been tested. Lastly, whether multiple expression mechanisms co-exist within a synapse or occur at distinct subsets of synapses remains to be determined.