Action Potential-Independent and Nicotinic Receptor-Mediated Concerted Release of Multiple Quanta at Hippocampal CA3–Mossy Fiber Synapses

Abstract

Presynaptic action potential-independent transmitter release is a potential means of information transfer across synapses. We show that in the hippocampal mossy fiber boutons, activation of the ␣7-subtype of nicotinic acetylcholine receptors (␣7-nAChRs) results in a large increase in the amplitude of spontaneous events, resulting from concerted release of multiple quanta from the mossy fiber boutons. This amplitude increase is abolished at low temperatures. Activation of ␣7-nAChRs causes a rise in intraterminal calcium at mossy fiber boutons, involving ryanodine receptors. Regulation of concerted release requires the subsequent activation of presynaptic calcium/ calmodulin-dependent protein kinase II (CaMKII). Activation of CaMKII is required to drive presynaptic action potential-independent transmission at the mossy fiber-CA3 pyramidal cell synapse. The effects of ␣7-nAChR activation are mediated by biologically relevant doses of nicotine. Our results demonstrate a novel form of synaptic plasticity mediated by presynaptic ␣7-nAChRs and store calcium that is temporally different and might respond to a different history of synaptic activity than that mediated by incoming action potentials.

Presynaptic α4β2 Nicotinic Acetylcholine Receptors Increase Glutamate Release and Serotonin Neuron Excitability in the Dorsal Raphe Nucleus

“…In contrast, Ca 2ϩ influx through presynaptic ␣7 nAChRs is sufficient to induce CICR and neurotransmitter release without the intervention of VGCCs (Gray et al, 1996;Sharma and Vijayaraghavan, 2003;Sharma et al, 2008). Accordingly, our data indicate that blocking N-, P/Q-, and L-type Ca 2ϩ channels by using selective The circles at zero current represent synaptic failures.…”

“…It should be mentioned that nicotineinduced glutamate release is more frequently mediated by ␣7 nAChRs than other nAChRs subtypes (McGehee et al, 1995;Girod and Role, 2001;Maggi et al, 2004;Sharma et al, 2008). However, in a few brain areas, non-␣7 nAChRs have also been involved in glutamate release modulation (Rousseau et al, 2005;Couey et al, 2007), and it has been reported that ␣4␤2 nAChRs facilitate glutamate release in thalamocortical afferents (Gioanni et al, 1999;Lambe et al, 2003).…”

“…8), nicotine activates more nAChRs and is degraded much slower than ACh. As a consequence, nicotine will induce a higher Ca 2ϩ influx, resulting in CICR, activation of Ca 2ϩ -dependent kinases (Dickinson et al, 2008;Sharma et al, 2008), and enhancement of synaptic efficacy at glutamate terminals. Once the changes in the synaptic release efficacy have occurred, they will extend beyond nAChR desensitization.…”

Vesicular Zinc Regulates the Ca2+Sensitivity of a Subpopulation of Presynaptic Vesicles at Hippocampal Mossy Fiber Terminals

“…Although the prominent skewed distribution of sEPSCs is generally thought to result from action-potential-mediated synchronization of different release sites, explanation of similar distribution pattern of mEPSCs is more challenging. Calcium release from intracellular stores underlies large-amplitude mIPSCs and presynaptic receptor-activated mEPSCs (Llano et al, 2000;Sharma and Vijayaraghavan, 2003;Gordon and Bains, 2005;Sharma et al, 2008). However, it is not known how large-amplitude mEPSCs are generated under control conditions.…”

Presynaptic α7- and β2-Containing Nicotinic Acetylcholine Receptors Modulate Excitatory Amino Acid Release from Rat Prefrontal Cortex Nerve Terminals via Distinct Cellular Mechanisms

“…However, Ca 2ϩ entry can further augment intracellular Ca 2ϩ concentration by Ca 2ϩ -induced Ca 2ϩ release (CICR) from internal Ca 2ϩ stores, via Ca 2ϩ release channels: notably, ryanodine receptors, and also inositol 1,4,5-trisphosphate receptors (Verkhratsky, 2005;Bardo et al, 2006). Indeed, increases in Ca 2ϩ in response to ␣7 nAChR activation are amplified by CICR in diverse preparations (Dajas-Bailador and Wonnacott, 2004), including hippocampal mossy fiber terminals (Sharma et al, 2008) and neuronal cell lines (Dickinson et al, 2007).…”