α-Synuclein Aggregates Increase the Conductance of Substantia Nigra Dopamine Neurons, an Effect Partly Reversed by the KATP Channel Inhibitor Glibenclamide

Hill, Emily; Gowers, Robert; Richardson, Magnus J. E.; Wall, Mark J.

doi:10.1523/eneuro.0330-20.2020

Cited by 20 publications

(19 citation statements)

References 46 publications

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“…In particular the changes in action potential amplitude and waveform kinetics. In previous studies (11,19,20) and in this study we have carried out a number of control experiments that have allowed us to reject this possibility. These controls include monitoring of series resistance throughout recordings and adjusting the bridge balance as required, introducing large concentrations of a control protein (BSA, 20 μM vs 44-144 nM) into neurons and observing no change in series resistance, repatching neurons (with vehicle in the patch solution) which had been injected with tau oligomers and showing that the changes in action potential waveform persisted (11).…”

Section: Discussionmentioning

confidence: 97%

“…In this study we have found that it is the smallest fragment of the tau oligomer that has the greatest effects on action waveform, which is the opposite to what would be expected if it was just the tau oligomers non-specifically blocking the pipette tip. We have also previously investigated the effects of alpha-synuclein oligomers on neuronal properties by introducing them via the patch pipette (19). These oligomers are much larger than the tau oligomers but had no effect on the action potential amplitude or waveform kinetics (19).…”

Section: Discussionmentioning

confidence: 99%

“…FL-oTau had comparable effects to those previously reported in (11): increasing input resistance, increasing neuronal firing rate (a correlate of neuronal excitability) and changing the action potential waveform (reducing height, amplitude relative to baseline, and increasing width). These effects were specific to oligomers, with monomeric FL-oTau having no significant effects (11) and are not the result of the tau oligomers blocking the tip of the recording pipette, as a number of controls have previously been carried out to eliminate this possibility (11,19,20).…”

Section: Removing the N-terminal Region Of Tau (Aa 1-123) Abolishes The Effects Of Tau On Action Potential Waveform And Input Resistance mentioning

confidence: 99%

“…This approach only requires small amounts of oligomers, each cell acts as its own control and electrophysiological alterations can be observed in real time. Furthermore, direct comparisons can be made between different concentrations and structural conformations of the oTau introduced (11,19,20).…”

Section: Introductionmentioning

confidence: 99%

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Truncating Tau Reveals Different Pathophysiological Actions of Oligomers in Single Neurons

Hill

Karikari

Lantero‐Rodriguez

et al. 2021

Preprint

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Tau protein is involved in maintaining the structural integrity of neurons. In tauopathies, including Alzheimer's disease, tau forms oligomers, which can modulate neuronal function. Previously the introduction of oligomeric full-length human tau (aa 1-441; FL-oTau) into pyramidal neurons decreased whole-cell conductance, increased excitability and changed the action potential (AP) waveform. Introducing N-terminally truncated tau (aa 124-441; CFRAG) removed the effects on the AP waveform and input resistance but the increase in excitability remained. A hyperpolarising shift in spike threshold underlies this increase in excitability. The N-terminal fragment (aa 1-123; NFRAG) markedly increased input resistance and changed the AP waveform. Lower concentrations of NFRAG only changed the AP waveform. Thus the two truncations can recapitulate the effects of FL-oTau. To investigate underlying mechanisms, we recorded sodium currents and found that FL-oTau lowers the activation voltage and reduced the maximal conductance, consistent with the lower spike threshold and reduction in AP amplitude.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Removing the N-terminal Region Of Tau (Aa 1-123) Abolishes The Effects Of Tau On Action Potential Waveform And Input Resistance mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Truncating Tau Reveals Different Pathophysiological Actions of Oligomers in Single Neurons

Hill

Karikari

Lantero‐Rodriguez

et al. 2021

Preprint

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“…Accumulation of α-syn aggregates may chronically activate KATP channels leading to loss of excitability and dopamine release [162].…”

Section: α-Synuclein Models Positive Effect On Exocytosis Negative Effect On Exocytosismentioning

confidence: 99%

Alpha-Synuclein and Lipids: The Elephant in the Room?

Sarchione

Marchand

Taymans

et al. 2021

Cells

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Since the initial identification of alpha-synuclein (α-syn) at the synapse, numerous studies demonstrated that α-syn is a key player in the etiology of Parkinson’s disease (PD) and other synucleinopathies. Recent advances underline interactions between α-syn and lipids that also participate in α-syn misfolding and aggregation. In addition, increasing evidence demonstrates that α-syn plays a major role in different steps of synaptic exocytosis. Thus, we reviewed literature showing (1) the interplay among α-syn, lipids, and lipid membranes; (2) advances of α-syn synaptic functions in exocytosis. These data underscore a fundamental role of α-syn/lipid interplay that also contributes to synaptic defects in PD. The importance of lipids in PD is further highlighted by data showing the impact of α-syn on lipid metabolism, modulation of α-syn levels by lipids, as well as the identification of genetic determinants involved in lipid homeostasis associated with α-syn pathologies. While questions still remain, these recent developments open the way to new therapeutic strategies for PD and related disorders including some based on modulating synaptic functions.

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Morpho‐Functional Changes of Nigral Dopamine Neurons in an α‐Synuclein Model of Parkinson's Disease

et al. 2022

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Background: The accumulation of α-synuclein (α-syn) fibrils in intraneuronal inclusions called Lewy bodies and Lewy neurites is a pathological signature of Parkinson's disease (PD). Although several aspects linked to α-syn-dependent pathology (concerning its spreading, aggregation, and activation of inflammatory and neurodegenerative processes) have been under intense investigation, less attention has been devoted to the real impact of α-syn overexpression on structural and functional properties of substantia nigra pars compacta (SNpc) dopamine (DA) neurons, particularly at tardive stages of α-syn buildup, despite this has obvious relevance to comprehending mechanisms beyond PD progression. Objectives: We aimed to determine the consequences of a prolonged α-syn overexpression on somatodendritic morphology and functions of SNpc DA neurons. Methods: We performed immunohistochemistry, stereological DA cell counts, analyses of dendritic arborization, ex vivo patch-clamp recordings, and in vivo DA microdialysis measurements in a 12-to 13-month-old transgenic rat model overexpressing the full-length human α-syn (Snca +/+ ) and age-matched wild-type rats.Results: Aged Snca +/+ rats have mild loss of SNpc DA neurons and decreased basal DA levels in the SN. Residual nigral DA neurons display smaller soma and compromised dendritic arborization and, in parallel, increased firing activity, switch in firing mode, and hyperexcitability associated with hypofunction of fast activating/ inactivating voltage-gated K + channels and Ca 2+ -and voltage-activated large conductance K + channels. These intrinsic currents underlie the repolarization/ afterhyperpolarization phase of action potentials, thus affecting neuronal excitability. Conclusions: Besides clarifying α-syn-induced pathological landmarks, such evidence reveals compensatory functional mechanisms that nigral DA neurons could adopt during PD progression to counteract neurodegeneration.

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α-Synuclein Aggregates Increase the Conductance of Substantia Nigra Dopamine Neurons, an Effect Partly Reversed by the KATP Channel Inhibitor Glibenclamide

Abstract: Alpha-synuclein aggregates increase the conductance of substantia nigra dopamine neurons, an effect partly reversed by the KATP channel inhibitor glibenclamide.

Cited by 20 publications

References 46 publications

Truncating Tau Reveals Different Pathophysiological Actions of Oligomers in Single Neurons

Truncating Tau Reveals Different Pathophysiological Actions of Oligomers in Single Neurons

Alpha-Synuclein and Lipids: The Elephant in the Room?

Morpho‐Functional Changes of Nigral Dopamine Neurons in an α‐Synuclein Model of Parkinson's Disease

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