A Specific Role for Ca²⁺-Dependent Adenylyl Cyclases in Recovery from Adaptive Presynaptic Silencing

Abstract

Glutamate generates fast postsynaptic depolarization throughout the CNS. The positive-feedback nature of glutamate signaling likely necessitates flexible adaptive mechanisms that help prevent runaway excitation. We have previously explored presynaptic adaptive silencing, a form of synaptic plasticity produced by ongoing neuronal activity and by strong depolarization. Unsilencing mechanisms that maintain active synapses and restore normal function after adaptation are also important, but mechanisms underlying such presynaptic reactivation remain unexplored. Here we investigate the involvement of the cAMP pathway in the basal balance between silenced and active synapses, as well as the recovery of baseline function after depolarization-induced presynaptic silencing. Activation of the cAMP pathway activates synapses that are silent at rest, and pharmacological inhibition of cAMP signaling silences basally active synapses. Adenylyl cyclase (AC) 1 and AC8, the major Ca 2ϩ -sensitive AC isoforms, are not crucial for the baseline balance between silent and active synapses. In cells from mice doubly deficient in AC1 and AC8, the baseline percentage of active synapses was only modestly reduced compared with wild-type synapses, and forskolin unsilencing was similar in the two genotypes. Nevertheless, after strong presynaptic silencing, recovery of normal function was strongly inhibited in AC1/AC8-deficient synapses. The entire recovery phenotype of the double null was reproduced in AC8-deficient but not AC1-deficient cells. We conclude that, under normal conditions, redundant cyclase activity maintains the balance between presynaptically silent and active synapses, but AC8 plays a particularly important role in rapidly resetting the balance of active to silent synapses after adaptation to strong activity.

Multilevel control of glucose homeostasis by adenylyl cyclase 8

“…Whereas sAC could be involved in mitochondrial generation of coupling factors, ADCY8 is required for sufficient increases in [Ca 2+ ] i . ADCY8, moreover, acts on a late step in exocytosis, as shown by capacitance measurements [6,33], its presynaptic expression in neurons [42] and the altered docking of synaptic vesicles in ADCY8 knockout mice [43].…”

Adenylyl cyclase 8 is central to glucagon-like peptide 1 signalling and effects of chronically elevated glucose in rat and human pancreatic beta cells

“…Although ADCY8 constitutes only a minor adenylyl cyclases [29,33], its expression was required for cAMP-induced amplification of exocytosis. The observed defect may reside in vesicle priming, reminiscent of the specific role of ADCY8 in hippocampal synapses despite the presence of calciumsensitive ADCY1 [47].…”

LRRK2 Controls Synaptic Vesicle Storage and Mobilization within the Recycling Pool

“…Therefore, if in basal condition the lack of LRRK2 might confer to vesicles a higher probability to contact the membrane and fuse, it might affect the organization of the presynaptic machinery as well, thus impairing SV mobilization required during high activity. An intriguing possibility yet to be explored is that the impact of LRRK2 on SV trafficking mainly interests silent synapses (Moulder et al, 2004(Moulder et al, , 2006(Moulder et al, , 2008 or the pool of reluctant vesicles described in glutamatergic terminals (Sun and Wu, 2001;Moulder and Mennerick, 2005). In fact, interestingly, LRRK2 knockdown and hypertonic sucrose stimulation were associated with a comparable increase in the ratio of recycling synapses.…”