The Type 2 Diabetes Factor Methylglyoxal Mediates Axon Initial Segment Shortening and Alters Neuronal Function at the Cellular and Network Levels

• Published in: eNeuro Vol. 8; no. 5; p. ENEURO.0201-21.2021
• Main Authors: Griggs, Ryan B, Nguyen, Duc V M, Yermakov, Leonid M, Jaber, Jeneane M, Shelby, Jennae N, Steinbrunner, Josef K, Miller, John A, Gonzalez-Islas, Carlos, Wenner, Peter, Susuki, Keiichiro
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 01-09-2021
• Subjects: Animals; Axon Initial Segment; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Female; Male; Mice; Neurons; New Research; Pyruvaldehyde; axon initial segment; methylglyoxal; network activity; type 2 diabetes; multielectrode array; depolarization
• ISSN: 2373-2822; 2373-2822
• DOI: 10.1523/eneuro.0201-21.2021

Recent evidence suggests that alteration of axon initial segment (AIS) geometry (i.e., length or location along the axon) contributes to CNS dysfunction in neurological diseases. For example, AIS length is shorter in the prefrontal cortex of type 2 diabetic mice with cognitive impairment. To determine the key type 2 diabetes-related factor that produces AIS shortening we modified levels of insulin, glucose, or the reactive glucose metabolite methylglyoxal in cultures of dissociated cortices from male and female mice and quantified AIS geometry using immunofluorescent imaging of the AIS proteins AnkyrinG and βIV spectrin. Neither insulin nor glucose modification altered AIS length. Exposure to 100 but not 1 or 10 μm methylglyoxal for 24 h resulted in accumulation of the methylglyoxal-derived advanced glycation end-product hydroimidazolone and produced reversible AIS shortening without cell death. Methylglyoxal-evoked AIS shortening occurred in both excitatory and putative inhibitory neuron populations and in the presence of tetrodotoxin (TTX). In single-cell recordings resting membrane potential was depolarized at 0.5-3 h and returned to normal at 24 h. In multielectrode array (MEA) recordings methylglyoxal produced an immediate ∼300% increase in spiking and bursting rates that returned to normal within 2 min, followed by a ∼20% reduction of network activity at 0.5-3 h and restoration of activity to baseline levels at 24 h. AIS length was unchanged at 0.5-3 h despite the presence of depolarization and network activity reduction. Nevertheless, these results suggest that methylglyoxal could be a key mediator of AIS shortening and disruptor of neuronal function during type 2 diabetes.