Differential Presynaptic ATP Supply for Basal and High-Demand Transmission

Abstract

The relative contributions of glycolysis and oxidative phosphorylation to neuronal presynaptic energy demands are unclear. In rat hippocampal neurons, ATP production by either glycolysis or oxidative phosphorylation alone sustained basal evoked synaptic transmission for up to 20 min. However, combined inhibition of both ATP sources abolished evoked transmission. Neither action potential propagation failure nor depressed Ca 2ϩ influx explained loss of evoked synaptic transmission. Rather, inhibition of ATP synthesis caused massive spontaneous vesicle exocytosis, followed by arrested endocytosis, accounting for the disappearance of evoked postsynaptic currents. In contrast to its weak effects on basal transmission, inhibition of oxidative phosphorylation alone depressed recovery from vesicle depletion. Local astrocytic lactate shuttling was not required. Instead, either ambient monocarboxylates or neuronal glycolysis was sufficient to supply requisite substrate. In summary, basal transmission can be sustained by glycolysis, but strong presynaptic demands are met preferentially by oxidative phosphorylation, which can be maintained by bulk but not local monocarboxylates or by neuronal glycolysis.

Limited distal organelles and synaptic function in extensive monoaminergic innervation

“…Thus, the absence of distal mitochondria may contribute to the lower efficiency of distal neuropeptide release and endocytosis that occurs as part of the SSV cycle (Fig. 2), which is known to be affected by mitochondria under high demand conditions (Rangaraju et al, 2014;Pathak et al, 2015;Sobieski et al, 2017). Together, the results presented here demonstrate deficient accumulation of two types of organelles -DCVs and mitochondria -and attenuated synaptic function at the most distal sites of extensive monoaminergic innervation.…”

“…Interestingly, endocytosis for SSV recycling and 'kiss-and-run' exocytosis for synaptic neuropeptide release both involve dynamin (Holz, 2013;Wong et al, 2015). Furthermore, in part because of dynamin, SSV recycling is a major consumer of ATP, which is provided by mitochondria when transmission is intense (Rangaraju et al, 2014;Pathak et al, 2015;Sobieski et al, 2017). Therefore, it will be of interest to test the hypothesis that the lower abundance of distal mitochondria limits dynamin function to diminish both endocytosis and neuropeptide release.…”

Mechanisms for the maintenance and regulation of axonal energy supply

“…These studies demonstrate that both glycolysis and oxphos contribute to presynaptic function by generating ATP in an activity‐dependent manner. Similarly, Sobieski et al found that simultaneous inhibition of both glycolysis and oxphos is required to achieve complete inhibition of evoked synaptic transmission (Sobieski, Fitzpatrick, & Mennerick, ). Therefore, it is likely that both oxphos and aerobic glycolysis contribute to synaptic energy metabolism and offer redundancies that confer energetic flexibility for synaptic activity.…”

“…These studies demonstrate that both glycolysis and oxphos contribute to presynaptic function by generating ATP in an activity-dependent manner. Similarly, Sobieski et al found that simultaneous inhibition of both glycolysis and oxphos is required to achieve complete inhibition of evoked synaptic transmission (Sobieski, Fitzpatrick, & Mennerick, 2017).…”

“…Considering the heterogenous findings between intracellular compartments and resting versus stimulated nerve cells, it seems imperative to interpret results only within the context measured. For example, in axonal terminals, where presynapses are located, synaptic activity imposes large energetic demands that are met by local ATP synthesis via glycolysis and oxidative phosphorylation (Ashrafi & Ryan, ; Ivannikov et al, ; Rangaraju et al, ; Sheng, ; Sobieski et al, ; Sun et al, ; Verstreken et al, ). To date, the relative contribution of oxphos versus glycolysis within the axonal compartment has not been reported.…”