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

2021 ◽  
Author(s):  
Ryan B. Griggs ◽  
Duc V.M. Nguyen ◽  
Leonid M. Yermakov ◽  
Jeneane M. Jaber ◽  
Jennae N. Shelby ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Neuronal Network ◽  
Initial Segment ◽  
Inhibitory Neuron ◽  
Axon Initial Segment ◽  
Network Activity ◽  
Related Factor ◽  
Neuronal Network Activity ◽  
Reactive Carbonyl Species

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.

scholarly journals The type 2 diabetes factor methylglyoxal mediates axon initial segment shortening and alters neuronal function at the cellular and network levels

eNeuro ◽  
2021 ◽  
pp. ENEURO.0201-21.2021
Author(s):  
Ryan B. Griggs ◽  
Duc V.M. Nguyen ◽  
Leonid M. Yermakov ◽  
Jeneane M. Jaber ◽  
Jennae N. Shelby ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Initial Segment ◽  
Axon Initial Segment ◽  
Neuronal Function

Small domain, large consequences: the axon initial segment as a key player in neuronal excitability

Neuroforum ◽  
2019 ◽  
Vol 25 (1) ◽  
pp. 49-60 ◽  
Author(s):  
Maren Engelhardt ◽  
Nora Jamann ◽  
Winnie Wefelmeyer
Keyword(s):  
Initial Segment ◽  
Neuronal Excitability ◽  
Axon Initial Segment ◽  
Fine Tuning ◽  
Network Activity ◽  
Neuronal Function ◽  
Neuronal Network Activity ◽  
Small Domain ◽  
The 1960S

Abstract The axon initial segment (AIS) is a crucial axonal domain for neuronal function – it allows neurons to generate action potentials, maintain their polarity or modulate their own excitability, thereby adapting to sudden and more long-term changes in network state. Although the AIS has been a well-described structure in neurons with work dating back to the 1960s, its fundamental role in neuronal function has only really been appreciated in the last decade. It is therefore no surprise that the AIS now also emerges as a hub for the onset of various pathophysiological conditions. In this review, we will focus on AIS development, function, and plasticity in the context of neuronal network activity and will highlight recent results that indicate a role for the AIS in the regulation and fine-tuning of input-output relations in single neurons.

scholarly journals Type 2 Diabetes Leads to Axon Initial Segment Shortening in db/db Mice

2018 ◽  
Vol 12 ◽  
Author(s):  
Leonid M. Yermakov ◽  
Domenica E. Drouet ◽  
Ryan B. Griggs ◽  
Khalid M. Elased ◽  
Keiichiro Susuki
Keyword(s):  
Type 2 Diabetes ◽  
Initial Segment ◽  
Axon Initial Segment

Desynchronisation of neuronal network activity in traumatic brain injury

2008 ◽  
Vol 39 (01) ◽  
Author(s):  
F Otto ◽  
J Opatz ◽  
R Hartmann ◽  
D Willbold ◽  
E Donauer ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neuronal Network ◽  
Network Activity ◽  
Neuronal Network Activity

Dementia with Lewy bodies—associated ß-synuclein mutations V70M and P123H cause mutation-specific neuropathological lesions

2021 ◽  
Author(s):  
Maryna Psol ◽  
Sofia Guerin Darvas ◽  
Kristian Leite ◽  
Sameehan U Mahajani ◽  
Mathias Bähr ◽  
...  
Keyword(s):  
Neuronal Network ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Sporadic Case ◽  
Network Activity ◽  
Proteinase K ◽  
Neuronal Network Activity ◽  
Distinct Disease

Abstract ß-Synuclein (ß-Syn) has long been considered to be an attenuator for the neuropathological effects caused by the Parkinson’s disease-related α-Synuclein (α-Syn) protein. However, recent studies demonstrated that overabundant ß-Syn can form aggregates and induce neurodegeneration in CNS neurons in vitro and in vivo, albeit at a slower pace as compared to α-Syn. Here we demonstrate that ß-Syn mutants V70M, detected in a sporadic case of Dementia with Lewy Bodies (DLB), and P123H, detected in a familial case of DLB, robustly aggravate the neurotoxic potential of ß-Syn. Intriguingly, the two mutations trigger mutually exclusive pathways. ß-Syn V70M enhances morphological mitochondrial deterioration and degeneration of dopaminergic and non-dopaminergic neurons, but has no influence on neuronal network activity. Conversely, ß-Syn P123H silences neuronal network activity, but does not aggravate neurodegeneration. ß-Syn WT, V70M and P123H formed proteinase K (PK) resistant intracellular fibrils within neurons, albeit with less stable C-termini as compared to α-Syn. Under cell free conditions, ß-Syn V70M demonstrated a much slower pace of fibril formation as compared to WT ß-Syn, and P123H fibrils present with a unique phenotype characterized by large numbers of short, truncated fibrils. Thus, it is possible that V70M and P123H cause structural alterations in ß-Syn, that are linked to their distinct neuropathological profiles. The extent of the lesions caused by these neuropathological profiles is almost identical to that of overabundant α-Syn, and thus likely to be directly involved into etiology of DLB. Over all, this study provides insights into distinct disease mechanisms caused by mutations of ß-Syn.

scholarly journals Homeostatic plasticity rules control the wiring of axo-axonic synapses at the axon initial segment

2018 ◽  
Author(s):  
Alejandro Pan-Vazquez ◽  
Winnie Wefelmeyer ◽  
Victoria Gonzalez Sabater ◽  
Juan Burrone
Keyword(s):  
Initial Segment ◽  
Pyramidal Cells ◽  
Axon Initial Segment ◽  
Homeostatic Plasticity ◽  
Network Activity ◽  
Gabaergic Interneuron ◽  
Chandelier Cells ◽  
Local Circuits ◽  
And Function

AbstractGABAergic interneurons are chiefly responsible for controlling the activity of local circuits in the cortex1,2. However, the rules that govern the wiring of interneurons are not well understood3. Chandelier cells (ChCs) are a type of GABAergic interneuron that control the output of hundreds of neighbouring pyramidal cells through axo-axonic synapses which target the axon initial segment (AIS)4. Despite their importance in modulating circuit activity, our knowledge of the development and function of axo-axonic synapses remains elusive. In this study, we investigated the role of activity in the formation and plasticity of ChC synapses. In vivo imaging of ChCs during development uncovered a narrow window (P12-P18) over which axons arborized and formed connections. We found that increases in the activity of either pyramidal cells or individual ChCs during this temporal window resulted in a reversible decrease in axo-axonic connections. Voltage imaging of GABAergic transmission at the AIS showed that axo-axonic synapses were depolarising during this period. Identical manipulations of network activity in older mice (P40-P46), when ChC synapses are inhibitory, resulted in an increase in axo-axonic synapses. We propose that the direction of ChC plasticity follows homeostatic rules that depend on the polarity of axo-axonic synapses.

Influence of albumin dialysis (MARS) on neuronal network activity in vitro

2001 ◽  
Vol 39 ◽  
pp. 40-40
Author(s):  
J Loock ◽  
J Stange ◽  
S Mitzner ◽  
R Schmidt ◽  
E W Keefer ◽  
...  
Keyword(s):  
Neuronal Network ◽  
Network Activity ◽  
Albumin Dialysis ◽  
Neuronal Network Activity
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