Glycolysis selectively shapes the presynaptic action potential waveform.

Area of Science:

• Neuroscience
• Cellular Biology
• Bioenergetics

Background:

• Mitochondria are key energy suppliers in neurons, but the role of glycolysis versus mitochondrial oxidative phosphorylation (OxPhos) in presynaptic energy utilization during neurotransmission is unclear.
• Understanding presynaptic energy metabolism is crucial for comprehending neuronal function and dysfunction.

Purpose of the Study:

• To investigate the distinct roles of glycolysis and mitochondrial OxPhos in regulating presynaptic function during neurotransmission.
• To determine how inhibiting these energy pathways affects action potential waveform, calcium influx, and synaptic transmission.

Main Methods:

• Utilized presynaptic and postsynaptic recordings from the mouse calyx of Held.
• Employed acute, selective pharmacological inhibition of glycolysis (glucose depletion, iodoacetic acid) and mitochondrial OxPhos (pyruvate depletion, oligomycin).
• Combined experimental manipulations with ion channel modeling to analyze action potential (AP) waveform and calcium (Ca2+) influx.

Main Results:

• Inhibition of glycolysis, but not mitochondrial OxPhos, rapidly altered synaptic transmission, causing variable and oscillating responses.
• At reduced temperatures, glycolysis inhibition attenuated synaptic transmission by narrowing and broadening the presynaptic AP waveform, leading to reduced Ca2+ influx and excitatory postsynaptic currents (EPSCs).
• Mitochondrial OxPhos inhibition showed no significant effect on Ca2+ influx or AP waveform within 30 minutes.

Conclusions:

• Glycolysis, not mitochondrial OxPhos, is required to maintain basal synaptic transmission at the presynaptic terminal.
• Hypoglycemia-induced neurotransmission deficits may stem from a presynaptic mechanism involving altered APs due to impaired glycolysis.
• Proposed that glycolytic enzymes are localized near presynaptic membrane ATP-dependent ion pumps, facilitating rapid energy supply.