Plastic Elimination of Functional Glutamate Release Sites by Depolarization

Abstract

To examine persisting effects of depolarizing rises in extracellular potassium concentration ([K+](o)) on synapses, we depolarized cells to simulate ischemia-like rises in [K+](o). Elevated [K+](o) for 1-16 hr severely depressed glutamate signaling, while mildly depressing GABA transmission. The glutamate-specific changes were plastic over several hours and involved a decrease in the size of the pool of releasable vesicles. Rather than a reduction of the number of vesicles per release site, the change involved functional elimination of release sites. This change was clearly dissociable from a second effect, depressed probability of transmitter release, which was common to both glutamate and GABA transmission. Thus, while other recent evidence links alteration of the releasable pool size with changes in p(r), our results suggest the two can be independently manipulated. Selective depression of glutamate release may provide an adaptive mechanism by which neurons limit excitotoxicity.

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

“…We have shown previously that a wide range of depolarizing challenges, ranging from pathophysiological (Moulder et al, 2004) to physiological (Moulder et al, 2006), results in strong presynaptic silencing. Manipulation of spiking within the physiological range of activity requires several days to produce strong presynaptic silencing, whereas strong depolarization requires only hours to produce 70 -80% presynaptic silencing.…”

“…We have shown previously that, after strong, depolarization-induced presynaptic silencing, reactivation of synapses occurs over ϳ4 h (Moulder et al, 2004). Ca 2ϩ -sensitive adenylyl cyclases may be particularly important in resetting normal synaptic functioning after removal of the depolarizing challenge, a process important for the resumption of normal neuronal signaling and for resetting appropriate balance between excitation and inhibition.…”

“…Ca 2ϩ -sensitive adenylyl cyclases may be particularly important in resetting normal synaptic functioning after removal of the depolarizing challenge, a process important for the resumption of normal neuronal signaling and for resetting appropriate balance between excitation and inhibition. To test for a role of AC1/ AC8 in recovery from presynaptic silencing, we used a protocol of 16 h depolarization, which produces a level of silencing (ϳ80%) from which recovery is easily monitored (Moulder et al, 2004) (Fig. 7).…”

“…We have described a form of presynaptic adaptation by which glutamatergic presynaptic terminals respond to changes in activity with a binary adjustment in the release competence of their synaptic vesicles (Moulder et al, 2004(Moulder et al, , 2006. Presynaptic silencing operates at normal levels of activity.…”

“…Likewise, after presynaptic silencing, removal of the depolarizing stimulus should result in recovery of silenced synapses to an active state. Indeed, we have shown that recovery from strong presynaptic silencing requires ϳ4 h (Moulder et al, 2004). Although such recovery is presumably important for resumption of normal signaling after a depolarizing challenge, the mechanisms of synaptic activation and reactivation are primarily unexplored.…”