A subset of synaptic transmission events is coupled to acetyl coenzyme A production.

Vikram Jakkamsetti, Qian Ma, Juan M Pascual

Journal of neurophysiology 2022 Mar 01

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Biological principles sustain the inference that synaptic function is coupled to neural metabolism, but the precise relationship between these two activities is not known. For example, it is unclear whether all synaptic transmission events are uniformly dependent on metabolic flux. Most synapses use glutamate, and the principal metabolic function of the brain is glucose oxidation, which starts with glycolysis. Thus, we asked how glutamatergic synaptic currents are modified by partial deficiency of the main glycolytic enzyme pyruvate dehydrogenase (PDH), which generates the intermediary metabolism product acetyl coenzyme A (acetyl-CoA). Using brain slices obtained from mice that were genetically modified to harbor a behaviorally relevant degree of PDH suppression, we also asked whether such impact is indeed metabolic via the bypassing of PDH with a glycolysis-independent acetyl-CoA substrate. We analyzed spontaneous synaptic currents under recording conditions that minimize artificial metabolic augmentation. Principal component analysis identified synaptic charge transfer as the major difference between a subset of wild-type and PDH-deficiency (PDHD) postsynaptic currents. This was due to reduced charge transfer as well as diminished current rise and decay times. The alternate acetyl-CoA source acetate rapidly restored these features but only for events of large amplitude as revealed by correlational and kernel density analyses. Application of tetrodotoxin to block large-amplitude events evoked by action potentials removed synaptic event charge transfer and decay-time differences between wild-type and PDHD neurons. These results suggest that glucose metabolic flux and excitatory transmission are intimately coupled for synaptic events characterized by large current amplitude.NEW & NOTEWORTHY In all tissues, metabolism and excitation are coupled but the details of this relationship remain elusive. Using a brain-targeted genetic approach in mice, reduction of pyruvate dehydrogenase, a major gateway in glucose metabolism, leads to changes that affect the synaptic event charge associated primarily with large excitatory (i.e., glutamate mediated) synaptic potentials. This can be modified in the direction of normal using the alternative fuel acetate, indicating that this phenomenon depends on rapid metabolic flux.

Citation

Vikram Jakkamsetti, Qian Ma, Juan M Pascual. A subset of synaptic transmission events is coupled to acetyl coenzyme A production. Journal of neurophysiology. 2022 Mar 01;127(3):623-636