Maturation of a PKG-Dependent Retrograde Mechanism for Exoendocytic Coupling of Synaptic Vesicles

Abstract

At presynaptic terminals vesicular membranes are fused into plasma membrane upon exocytosis and retrieved by endocytosis. During a sustained high-frequency transmission, exoendocytic coupling is critical for the maintenance of synaptic transmission. Here, we show that this homeostatic coupling is supported by cGMP-dependent protein kinase (PKG) at the calyx of Held. This mechanism starts to operate after hearing onset during the second postnatal week, when PKG expression becomes upregulated in the brainstem. Pharmacological tests with capacitance measurements revealed that presynaptic PKG activity is supported by a retrograde signal cascade mediated by NO that is released by activation of postsynaptic NMDA receptors. Activation of PKG also upregulates phosphatidylinositol-4,5-bisphosphate, thereby accelerating endocytosis. Furthermore, presynaptic PKG activity upregulates synaptic fidelity during high-frequency transmission. We conclude that maturation of the PKG-dependent retrograde signal cascade strengthens the homeostatic plasticity for the maintenance of high-frequency synaptic transmission at the fast glutamatergic synapse.

GluA2-Lacking AMPA Receptors and Nitric Oxide Signaling Gate Spike-Timing–Dependent Potentiation of Glutamate Synapses in the Dorsal Raphe Nucleus

“…NO signaling can enhance glutamate release and induce tLTP by nitrosothiol generation in a number of proteins of the release machinery (Meffert et al 1996) or by activation of the presynaptic sGC/cGMP pathway (Neitz et al 2011; Eguchi et al 2012). Here, we find that pharmacological manipulations that increase cGMP level potentiate glutamate synapses and occlude tLTP.…”

The role of nitric oxide in pre-synaptic plasticity and homeostasis

“…A good deal of evidence has been gathered in recent years for its importance in mediating the actions of endogenous NO, predominantly at pre-synaptic locations (Garthwaite, 2010; Neitz et al, 2011; Eguchi et al, 2012; Bartus et al, 2013). …”

“…However, since cells in culture are immature, it raises the question of whether NO acts the same way in more mature cells. Nevertheless, a number of studies made on mature neurons in intact slices of hippocampus (O'Dell et al, 1991; Schuman and Madison, 1991), amygdala (Lange et al, 2012), neocortex (Hardingham and Fox, 2006; Sjostrom et al, 2007), the medial nucleus of the trapezoid body (Steinert et al, 2008; Eguchi et al, 2012), cerebellum (Qiu and Knopfel, 2007), and the ventral lateral medulla (Huang et al, 2003), lead to similar conclusions about the action of NO in mature cells, suggesting that NO retains its retrograde pre-synaptic action into adulthood.…”

“…Part of the solution to this problem at the Calyx is provided by linking vesicle recycling to retrograde release of post-synaptic NO. Activation of the post synaptic MNTB neurons is related to the level of NO production (Steinert et al, 2008), which then drives the level of pre-synaptic cGMP production and hence the level of PKG activity (Eguchi et al, 2012). Finally, activation of PKG up-regulates PIP2, which increases the rate of endocytosis (Eguchi et al, 2012).…”

The calyx of Held in the auditory system: Structure, function, and development

“…Developmental changes lead to faster endocytosis kinetics at the calyx, probably by tighter coupling between endocytosis machinery and the VGCCs (Yamashita et al, 2010). Endocytosis at mature calyx is also accelerated by Rho kinase (Taoufiq et al, 2013) and is subject to retrograde modulation by protein kinase G, which acts through postsynaptic NO pathway (Eguchi et al, 2012). Brain-derived neurotrophic factor inhibits slow and rapid forms of endocytosis at immature and mature calyces (Baydyuk et al, 2015).…”