Spontaneous transmitter release recruits postsynaptic mechanisms of long-term and intermediate-term facilitation in Aplysia

Abstract

Whereas short-term (minutes) facilitation at Aplysia sensory-motor neuron synapses is presynaptic, long-term (days) facilitation involves synaptic growth, which requires both presynaptic and postsynaptic mechanisms. How are the postsynaptic mechanisms recruited, and when does that process begin? We have been investigating the possible role of spontaneous transmitter release from the presynaptic neuron. In the previous paper, we found that spontaneous release is critical for the induction of long-term facilitation, and this process begins during an intermediate-term stage of facilitation that is the first stage to involve postsynaptic as well as presynaptic mechanisms. We now report that increased spontaneous release during the short-term stage acts as an orthograde signal to recruit postsynaptic mechanisms of intermediate-term facilitation including increased IP3, Ca 2+ , and membrane insertion and recruitment of clusters of AMPA-like receptors, which may be first steps in synaptic growth during long-term facilitation. These results suggest that the different stages of facilitation involve a cascade of pre-and postsynaptic mechanisms, which is initiated by spontaneous release and may culminate in synaptic growth.synaptic plasticity | metabotropic glutamate receptor | octopamine | latrotoxin | botulinum toxin W hereas short-term (minutes) facilitation in Aplysia involves covalent modifications restricted to the presynaptic neuron, long-term (days) facilitation is accompanied by the growth of new synapses, which involves coordinated pre-and postsynaptic structural changes (1-4). Those findings raise two questions that are applicable to other forms of plasticity that can involve synaptic growth, such as the late phase of long-term potentiation (LTP) in the hippocampus (5-9) and other brain areas: (i) What signaling mechanisms coordinate the pre-and postsynaptic changes, and (ii) when is that signaling first engaged?To address these questions, we have been investigating the possible role of spontaneous transmitter release from the presynaptic neuron in recruiting the postsynaptic mechanisms of long-term facilitation in Aplysia. We previously found that spontaneous transmitter release is critical for the induction of longterm facilitation (10) (in this issue of PNAS). In addition, we found that this signaling is engaged quite early, during an intermediate-term stage that incorporates elements of both shortand long-term plasticity (11, 12), and therefore might form part of a bridge or cascade connecting them. The intermediate stage is also the first stage to involve both presynaptic molecular mechanisms and postsynaptic mechanisms including IP3, Ca 2+ , protein synthesis, and membrane insertion of AMPA-like receptors (1, 2, 13, 14). Postsynaptic Ca 2+ and protein synthesis are in turn necessary for long-term facilitation, in part through retrograde signaling (15).We have now investigated mechanisms downstream of spontaneous release, and have found that it plays a critical role in recruitment of the postsynaptic mechan...

Spontaneous transmitter release is critical for the induction of long-term and intermediate-term facilitation inAplysia

“…2 A and B). We chose that paradigm because it has been used most extensively to study postsynaptic mechanisms of facilitation in Aplysia (23,33,34), and we wished to investigate how those mechanisms are recruited (31). The results were generally similar to those for long-term facilitation, except that there was a larger decrease in the test-alone control EPSPs due to homosynaptic depression, which is quite reliable at these synapses at stimulation intervals of 10 min or less.…”

Whereas short-term facilitation is presynaptic, intermediate-term facilitation involves both presynaptic and postsynaptic protein kinases and protein synthesis

“…Previous evidence suggested that prolonged exposure to 5-HT may act to inhibit 5-HT receptor-coupled adenylyl cyclase (Sugita et al 1992(Sugita et al , 1997. One possible reason would be that enhanced spontaneous transmitter release during prolonged exposure to 5HT (Jin et al 2007(Jin et al , 2008) may activate presynaptic type II or III metabotropic glutamate receptors, which are negatively coupled to adenylyl cyclase. Consistent with that idea, an inhibitor of type II and III metabotropic glutamate receptors, LY341495 (1 mM), significantly enhanced facilitation by 10-min, 20 mM 5-HT (P , 0.05 compared with DMSO control overall) (Fig.…”

“…One possibility is that the postsynaptic mechanisms are recruited in parallel with the presynaptic mechanisms by activation of pre-and postsynaptic 5HT receptors (Li et al 2005;Fulton et al 2008;Villareal et al 2007Villareal et al , 2009. Alternatively, recent studies have found that activation of presynaptic 5-HT receptors enhances spontaneous release of glutamate, which then activates metabotropic glutamate receptors to recruit the postsynaptic mechanisms of intermediate-term facilitation (Jin et al 2007(Jin et al , 2008 and initiate a cascade that may culminate in synaptic growth during long-term facilitation (Jin et al 2010). Those findings could explain why homosynaptic potentiation by tetanic stimulation of the presynaptic neuron (Jin and Hawkins 2003) involves some of the same postsynaptic mechanisms as intermediate-term Figure 2A1.…”

Presynaptic T-Type Ca2+Channels Modulate Dendrodendritic Mitral–Mitral and Mitral–Periglomerular Connections in Mouse Olfactory Bulb

“…Submicromolar increments of [Ca 2ϩ ] increase asynchronous transmitter release from many synapses (Zucker and Regehr, 2002). There is growing evidence for functional physiological effects of asynchronous release at a variety of synapses (Chávez et al, 2006;Best and Regehr, 2009;Jin et al, 2012), including accessory mitral apical tuft (Castro and Urban, 2009).…”