Molecular mechanisms driving homeostatic plasticity of neurotransmitter release

Abstract

Homeostatic plasticity is a process by which neurons adapt to the overall network activity to keep their firing rates in a reasonable range. At the cellular level this kind of plasticity comprises modulation of cellular excitability and tuning of synaptic strength. In this review we concentrate on presynaptic homeostatic plasticity controlling the efficacy of neurotransmitter release from presynaptic boutons. While morphological and electrophysiological approaches were successful to describe homeostatic plasticity-induced changes in the presynaptic architecture and function, cellular and molecular mechanisms underlying those modifications remained largely unknown for a long time. We summarize the latest progress made in the understanding of homeostasis-induced regulation of different steps of the synaptic vesicle cycle and the molecular machineries involved in this process. We particularly focus on the role of presynaptic scaffolding proteins, which functionally and spatially organize synaptic vesicle clusters, neurotransmitter release sites and the associated endocytic machinery. These proteins turned out to be major presynaptic substrates for remodeling during homeostatic plasticity. Finally, we discuss cellular processes and signaling pathways acting during homeostatic molecular remodeling and their potential involvement in the maladaptive plasticity occurring in multiple neuropathologic conditions such as neurodegeneration, epilepsy and neuropsychiatric disorders.

Experience-dependent regulation of presynaptic NMDARs enhances neurotransmitter release at neocortical synapses

“…The changes that are reported here are anti-homeostatic; they do not act to dampen the excitability of neurons in the face of increased sensory-evoked activity. This contrasts to other studies that have investigated the effect of decreased neural activity that enhances release probability (Bacci et al 2001;Murthy et al 2001;Desai et al 2002;Yashiro and Philpot 2008;Lazarevic et al 2013); it may be that homeostatic adjustments in release are engaged by decreased but not increased sensory-evoked activity, and are not fully bidirectional.…”

Homeostatic Control of Presynaptic Neurotransmitter Release

“…Conversely, prolonged exposure to elevated extracellular potassium concentration decreased RRP size and synaptic RIM levels (79). Thus, homeostatic signaling may affect synaptic RIM levels, as well as the levels of other presynaptic matrix-associated proteins (15). A current model suggests the activity-dependent modulation of the presynaptic ubiquitin proteasome system (15).…”

“…Thus, homeostatic signaling may affect synaptic RIM levels, as well as the levels of other presynaptic matrix-associated proteins (15). A current model suggests the activity-dependent modulation of the presynaptic ubiquitin proteasome system (15).…”

“…This review focuses exclusively on the homeostatic modulation of presynaptic neurotransmitter release, an evolutionarily conserved form of homeostatic control observed at synapses in systems that are as diverse as the glutamatergic neuromuscular junction (NMJ) of insects, the cholinergic NMJ of vertebrates, and central synapses throughout the mammalian brain (Figure 1a). Recent reviews have examined the literature regarding other aspects of homeostatic plasticity (13)(14)(15)(16)(17).…”

Neuronal hyperactivity causes Na+/H+ exchanger-induced extracellular acidification at active synapses

“…The synaptic distribution of acidic shifts emphasizes that an alteration of synaptic transmission is the first step for the initiation and maintenance of ictal activity (Lazarevic et al, 2013). Release of SV protons into the synaptic cleft upon intense exocytosis has been recently proposed as a mechanism of protonergic transmission (Du et al, 2014;Wang et al, 2014).…”