The Effects of Methylglyoxal on Central Synaptic Transmission in the Isolated Nerve Cord of the Cockroach (Periplaneta Americana L)

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 TTX. In single-cell recordings resting membrane potential was depolarized at 0.5-3 h and returned to normal at 24 h. In multi-electrode array 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. Significance StatementSmall changes in the structure of the axon initial segment affect neuronal function and may be a key mediator of neurological complications in various disease states. However, the specific disease factors that mediate structural changes at the axon initial segment are relatively unknown. This is the first study to show that increase of methylglyoxal is sufficient to reduce axon initial segment length and modulate neuronal function at the cellular and network levels. Methylglyoxal is a disease factor implicated in a wide variety of conditions including type 2 diabetes, Alzheimer's disease, and aging. Thus, these findings could significantly impact the understanding of neurological complications in several disease states and are of broad pathophysiological relevance.

show abstract

Section: Are Ais Geometry and Neuronal Function Linked?mentioning

confidence: 99%

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

Griggs

Nguyen

Yermakov

et al. 2021

eNeuro

View full text Add to dashboard Cite

show abstract

“…For example, homeostatic increase of synaptic input could lead to recovery of network activity despite AIS shortening. Indeed, methylglyoxal increases both evoked and spontaneous excitatory postsynaptic potentials in cockroach abdominal ganglia (Chambers et al, 1985), but whether it alters synaptic efficacy in mouse cortical neurons is unknown. Type 2 diabetic db/db mice show AIS shortening (Yermakov et al, 2018(Yermakov et al, , 2019, but there are also reports of altered synaptic plasticity (Li et al, 2002;Stranahan et al, 2008), decreased dendritic spine density (Stranahan et al, 2009;Chen et al, 2014), and progressive cortical atrophy (Ramos-Rodriguez et al, 2013).…”

Section: How Does Methylglyoxal Trigger Network Activity Changes and Ais Shortening?mentioning

confidence: 99%

The type 2 diabetes factor methylglyoxal mediates axon initial segment shortening and neuronal network activity changes

Griggs

et al. 2021

Preprint

View full text Add to dashboard Cite

Recent evidence suggests that alteration of axon initial segment (AIS) geometry (i.e., length or position 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. The key type 2 diabetes-related factor that alters AIS geometry is unknown. Here, we tested whether modifying the levels of insulin, glucose, or methylglyoxal, a reactive carbonyl species that is a metabolite of glucose, changes AIS geometry in mature cultures of dissociated postnatal mouse cortex using immunofluorescent imaging of the AIS proteins AnkyrinG and βIV spectrin. Neither insulin nor glucose modification appreciably altered AIS length. Elevation of methylglyoxal produced reversible AIS shortening without cell death. Multi-electrode array recordings revealed a biphasic effect of methylglyoxal on neuronal network activity: an immediate, transient ~300% increase in spiking and bursting rates was followed by a ~20% reduction from baseline at 3 h. AIS length was unchanged at 0.5 h or 3 h after adding methylglyoxal, whereas development of AIS shortening at 24 h was associated with restoration of spiking to baseline levels. Immunostaining for the excitatory neuron marker Ca2+/calmodulin-dependent protein kinase II alpha revealed AIS shortening in both excitatory and inhibitory neuron populations. This suggests that complex mechanisms maintain neuronal network operation after acute exposure to the disease metabolite methylglyoxal. Importantly, our results indicate that methylglyoxal could be a key mediator of AIS shortening during type 2 diabetes.

show abstract

Effects of Methylglyoxal on Central and Peripheral Cholinergic Responses

Davies

Chambers

Rowan

1986

Archives of Toxicology

View full text Add to dashboard Cite

The Effects of Methylglyoxal on Central Synaptic Transmission in the Isolated Nerve Cord of the Cockroach (Periplaneta Americana L)

Cited by 8 publications

References 6 publications

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

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

The type 2 diabetes factor methylglyoxal mediates axon initial segment shortening and neuronal network activity changes

Effects of Methylglyoxal on Central and Peripheral Cholinergic Responses

Contact Info

Product

Resources

About