Activity-dependent regulation of synapses by retrograde messengers

Abstract

Throughout the brain, postsynaptic neurons release substances from their cell bodies and dendrites that regulate the strength of the synapses they receive. Diverse chemical messengers have been implicated in retrograde signaling from postsynaptic neurons to presynaptic boutons. Here, we provide an overview of the signaling systems that lead to rapid changes in synaptic strength. We consider the capabilities, specializations, and physiological roles of each type of signaling system.

Figure 1. Representative signaling systems to illustrate retrograde signaling by different categories of messengers

A. General scheme of retrograde signaling in which a substance (green) is released on demand from the postsynaptic cell. (B–F). Examples for different classes of retrograde messengers. B. Lipid-derived retrograde signaling: glutamate release from the presynaptic bouton activates AMPA receptors to depolarize the postsynaptic cell and open voltage-gated calcium channels (VGCC), and metabotropic type 1 glutamate receptor (mGluR1) to activate the G-protein G_q. Together, calcium and G_q activate PLCβ which converts the lipid PIP₂ into DAG, which is converted into the endocannabinoid 2AG. 2AG then activates presynaptic CB1Rs, which in turn acts on presynaptic targets to reduce the probability of release. C. Retrograde signaling mediated by gases: activation of NMDARs leads to calcium entry, which activates neuronal nitric oxide synthase (nNOS) to produce NO release. NO affects release from presynaptic boutons either by activating sGC, which ultimately activates PKG, or by S-nitrosylating proteins in presynaptic boutons. D. Peptidergic retrograde signaling: calcium entry into the postsynaptic cell results in the fusion of dense core vesicles. Dynorphin is released and activates presynaptic kappa opioid receptors to reduce the probability of release. E. Retrograde signaling mediated by a conventional neurotransmitter: calcium increases in the postsynaptic cell result in the fusion of GABA-containing vesicles. GABA then activates presynaptic GABA_B receptors, thereby reducing the probability of release. F. Retrograde signaling mediated by growth factors: calcium entry into the postsynaptic cell results in the fusion of secretory granules. This results in the liberation of BDNF that activates presynaptic TrkB receptors to regulate the probability of release.

Figure 2. Calcium dependence of the release of a retrograde messenger

A number of studies have determined the calcium dependence of eCB release in control conditions (black curve). The ability of somatic activity to evoke eCB release from a cell can be regulated in two ways. First, the calcium dependence of release can be regulated. For example, mGluR1 activation promotes eCB release by lowering the calcium dependence of release (blue curve). Second, the dendritic calcium signal evoked by a given pattern of activity can be regulated. This is illustrated schematically by the light green and pink regions, which represent respectively dendritic calcium increases evoked by the same pattern of somatic activity in control conditions and in the presence of a neuromodulator that increases activity-dependent increases in dendritic calcium (ΔCa).

Figure 3. Factors governing the duration and spread of retrograde signals

Schematics illustrate the spread of retrograde messengers that do not readily permeate the membrane (A), such as conventional neurotransmitters, endocannabinoids, peptides and growth factors, and those that are membrane permeant (B), such as gases. (C–F) Examples that illustrate the uptake and degradation of different types of retrograde signals. C. Conventional neurotransmitters: excitatory amino acid transporters (EAATs) located on presynaptic neurons, postsynaptic neurons and glia restrict the spread and determine the duration of extracellular glutamate levels. D. Lipid derived messengers: Endocannabinoid signaling is regulated by a putative transporter whose location and identity are not known. The degradation of eCBs by monoglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH) also help to terminate the eCB signal. E. Peptides: Peptidases terminate peptide signaling by cleaving peptides. F. Growth factors: TrkB receptors located on presynaptic cells, postsynaptic cells and glia help terminate BDNF signaling. BDNF binding to TrkB receptors can result in endocytosis.

Figure 4. Physiological roles of retrograde signaling

A. Example of how retrograde signaling by eCBs contributes to spike-timing dependent plasticity at cortical synapses. Plasticity was induced by repeatedly pairing postsynaptic action potentials with synaptic activation, with the relative timing of the two stimuli systematically altered. In control conditions synaptic inputs prior to spiking result in LTP, whereas synaptic inputs that follow spiking result in LTD (black trace). Two components of plasticity are revealed by blocking NMDARs in the postsynaptic cell (red trace), and by blocking CB1Rs (blue trace). B. Retrograde signaling plays a role in homeostatic regulation at the Drosophila neuromuscular junction. gbb→WIT signaling is needed to permit retrograde signaling to occur, but it acts on long time scales, requires the soma and involves protein synthesis. Homeostatic plasticity appears to involve an unidentified retrograde messenger that acts on the minutes time scale. (C, D) Retrograde signaling plays a role in dynamic regulation of circuits. C. For example, in the hippocampus CA1 pyramidal cells suppress synapses from a specific class of interneurons, whereas synapses from other interneurons that do not contain CB1Rs are unaffected. D. In the cerebellum, granule cells make synapses onto different postsynaptic targets. The influence of granule cells on these targets can be very different and by virtue of the fact that PCs readily release eCBs, whereas Golgi cells do not.

Figure 5. Examples of complex interactions between signaling systems

A. Studies in the hypothalamus suggested that oxytocin is a retrograde messenger that activates presynaptic oxytocin receptors to reduce the probability of release. B. Subsequent studies indicate that oxytocin is not a retrograde messenger. Oxytocin activates postsynaptic oxytocin receptors that are coupled to G_q. They promote the release of an eCB (probably 2-AG), which is the actual retrograde messenger that acts presynaptically to reduce the probability of release. C. Example of the potential sources of BDNF and location of TrkB receptors. D. Genetic elimination of BDNF release specifically from presynaptic or postsynaptic cells established that presynaptic boutons are the source of BDNF required for LTP induction, and retrograde BDNF signaling is not involved.