PMID- 27605535
OWN - NLM
STAT- MEDLINE
DCOM- 20170908
LR  - 20181113
IS  - 1522-1598 (Electronic)
IS  - 0022-3077 (Print)
IS  - 0022-3077 (Linking)
VI  - 116
IP  - 6
DP  - 2016 Dec 1
TI  - Glycolysis selectively shapes the presynaptic action potential waveform.
PG  - 2523-2540
LID - 10.1152/jn.00629.2016 [doi]
AB  - Mitochondria are major suppliers of cellular energy in neurons; however, 
      utilization of energy from glycolysis vs. mitochondrial oxidative phosphorylation 
      (OxPhos) in the presynaptic compartment during neurotransmission is largely 
      unknown. Using presynaptic and postsynaptic recordings from the mouse calyx of 
      Held, we examined the effect of acute selective pharmacological inhibition of 
      glycolysis or mitochondrial OxPhos on multiple mechanisms regulating presynaptic 
      function. Inhibition of glycolysis via glucose depletion and iodoacetic acid (1 
      mM) treatment, but not mitochondrial OxPhos, rapidly altered transmission, 
      resulting in highly variable, oscillating responses. At reduced temperature, this 
      same treatment attenuated synaptic transmission because of a smaller and broader 
      presynaptic action potential (AP) waveform. We show via experimental manipulation 
      and ion channel modeling that the altered AP waveform results in smaller Ca(2+) 
      influx, resulting in attenuated excitatory postsynaptic currents (EPSCs). In 
      contrast, inhibition of mitochondria-derived ATP production via extracellular 
      pyruvate depletion and bath-applied oligomycin (1 muM) had no significant effect 
      on Ca(2+) influx and did not alter the AP waveform within the same time frame (up 
      to 30 min), and the resultant EPSC remained unaffected. Glycolysis, but not 
      mitochondrial OxPhos, is thus required to maintain basal synaptic transmission at 
      the presynaptic terminal. We propose that glycolytic enzymes are closely apposed 
      to ATP-dependent ion pumps on the presynaptic membrane. Our results indicate a 
      novel mechanism for the effect of hypoglycemia on neurotransmission. Attenuated 
      transmission likely results from a single presynaptic mechanism at reduced 
      temperature: a slower, smaller AP, before and independent of any effect on 
      synaptic vesicle release or receptor activity.
CI  - Copyright (c) 2016 the American Physiological Society.
FAU - Lujan, Brendan
AU  - Lujan B
AD  - Department of Physiology and Cell Biology, University of Nevada, Reno School of 
      Medicine, Reno, Nevada.
FAU - Kushmerick, Christopher
AU  - Kushmerick C
AD  - Departamento de Fisiologia e Biofisica, Instituto de Ciencias Biologicas, 
      Universidade Federal de Minas Gerais, Minas Gerais, Brazil; and.
FAU - Banerjee, Tania Das
AU  - Banerjee TD
AUID- ORCID: 0000-0003-0671-7670
AD  - Department of Pharmacology, University of Nevada, Reno School of Medicine, Reno, 
      Nevada.
FAU - Dagda, Ruben K
AU  - Dagda RK
AUID- ORCID: 0000-0002-9946-9591
AD  - Department of Pharmacology, University of Nevada, Reno School of Medicine, Reno, 
      Nevada.
FAU - Renden, Robert
AU  - Renden R
AUID- ORCID: 0000-0001-7905-4789
AD  - Department of Physiology and Cell Biology, University of Nevada, Reno School of 
      Medicine, Reno, Nevada; rendenr@unr.edu.
LA  - eng
GR  - P20 GM103554/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20160907
PL  - United States
TA  - J Neurophysiol
JT  - Journal of neurophysiology
JID - 0375404
RN  - 0 (Antimetabolites)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Indoleacetic Acids)
RN  - 0 (Luminescent Proteins)
RN  - 0 (Oligomycins)
RN  - 19817-95-9 (1-O-indol-3-ylacetylglucose)
RN  - 9G2MP84A8W (Deoxyglucose)
RN  - IY9XDZ35W2 (Glucose)
RN  - WF5188V710 (Iodoacetic Acid)
SB  - IM
MH  - Action Potentials/drug effects/*physiology
MH  - Animals
MH  - Animals, Newborn
MH  - Antimetabolites/pharmacology
MH  - Brain Stem/cytology
MH  - Cells, Cultured
MH  - Cerebral Cortex/cytology
MH  - Deoxyglucose/pharmacology
MH  - Embryo, Mammalian
MH  - Enzyme Inhibitors/pharmacology
MH  - Excitatory Postsynaptic Potentials/drug effects/physiology
MH  - Glucose/pharmacology
MH  - Glycolysis/drug effects/*physiology
MH  - Indoleacetic Acids/pharmacology
MH  - Iodoacetic Acid/pharmacology
MH  - Luminescent Proteins/genetics/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Models, Neurological
MH  - Neurons/drug effects
MH  - Oligomycins/pharmacology
MH  - Presynaptic Terminals/drug effects/*physiology
PMC - PMC5133309
OTO - NOTNLM
OT  - bioenergetics
OT  - calyx of Held
OT  - hypoglycemia
OT  - oxidative phosphorylation
OT  - stroke
EDAT- 2016/09/09 06:00
MHDA- 2017/09/09 06:00
PMCR- 2017/12/01
CRDT- 2016/09/09 06:00
PHST- 2016/08/08 00:00 [received]
PHST- 2016/09/05 00:00 [accepted]
PHST- 2016/09/09 06:00 [pubmed]
PHST- 2017/09/09 06:00 [medline]
PHST- 2016/09/09 06:00 [entrez]
PHST- 2017/12/01 00:00 [pmc-release]
AID - jn.00629.2016 [pii]
AID - JN-00629-2016 [pii]
AID - 10.1152/jn.00629.2016 [doi]
PST - ppublish
SO  - J Neurophysiol. 2016 Dec 1;116(6):2523-2540. doi: 10.1152/jn.00629.2016. Epub 
      2016 Sep 7.