scholarly journals The Stimulatory Effects of Intracellular α-Synuclein on Synaptic Transmission Are Attenuated by 2-Octahydroisoquinolin-2(1H)-ylethanamine

2021 ◽  
Vol 22 (24) ◽  
pp. 13253
Author(s):  
Alejandra E. Ramirez ◽  
Eduardo J. Fernández-Pérez ◽  
Nicol Olivos ◽  
Carlos F. Burgos ◽  
Subramanian Boopathi ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Synaptic Transmission ◽  
Hippocampal Neurons ◽  
Excitatory Effect ◽  
Synaptic Currents ◽  
Hydrophobic Region ◽  
Potent Effect ◽  
Synaptic Physiology ◽  
Presynaptic Site ◽  
Dynamics Simulations

α-Synuclein (αSyn) species can be detected in synaptic boutons, where they play a crucial role in the pathogenesis of Parkinson’s Disease (PD). However, the effects of intracellular αSyn species on synaptic transmission have not been thoroughly studied. Here, using patch-clamp recordings in hippocampal neurons, we report that αSyn oligomers (αSynO), intracellularly delivered through the patch electrode, produced a fast and potent effect on synaptic transmission, causing a substantial increase in the frequency, amplitude and transferred charge of spontaneous synaptic currents. We also found an increase in the frequency of miniature synaptic currents, suggesting an effect located at the presynaptic site of the synapsis. Furthermore, our in silico approximation using docking analysis and molecular dynamics simulations showed an interaction between a previously described small anti-amyloid beta (Aβ) molecule, termed M30 (2-octahydroisoquinolin-2(1H)-ylethanamine), with a central hydrophobic region of αSyn. In line with this finding, our empirical data aimed to obtain oligomerization states with thioflavin T (ThT) and Western blot (WB) indicated that M30 interfered with αSyn aggregation and decreased the formation of higher-molecular-weight species. Furthermore, the effect of αSynO on synaptic physiology was also antagonized by M30, resulting in a decrease in the frequency, amplitude, and charge transferred of synaptic currents. Overall, the present results show an excitatory effect of intracellular αSyn low molecular-weight species, not previously described, that are able to affect synaptic transmission, and the potential of a small neuroactive molecule to interfere with the aggregation process and the synaptic effect of αSyn, suggesting that M30 could be a potential therapeutic strategy for synucleinopathies.

Two Mechanisms That Raise Free Intracellular Calcium in Rat Hippocampal Neurons During Hypoosmotic and Low NaCl Treatment

2000 ◽  
Vol 83 (1) ◽  
pp. 81-89 ◽  
Author(s):  
Aren J. Borgdorff ◽  
George G. Somjen ◽  
Wytse J. Wadman
Keyword(s):  
Synaptic Transmission ◽  
Intracellular Calcium ◽  
Hippocampal Neurons ◽  
Pyramidal Neurons ◽  
Hippocampal Slices ◽  
Cell Swelling ◽  
Tissue Slices ◽  
Extracellular Medium ◽  
Calcium Activity ◽  
Hippocampal Pyramidal Neurons

Previous studies have shown that exposing hippocampal slices to low osmolarity (πo) or to low extracellular NaCl concentration ([NaCl]o) enhances synaptic transmission and also causes interstitial calcium ([Ca2+]o) to decrease. Reduction of [Ca2+]o suggests cellular uptake and could explain the potentiation of synaptic transmission. We measured intracellular calcium activity ([Ca2+]i) using fluorescent indicator dyes. In CA1 hippocampal pyramidal neurons in tissue slices, lowering πo by ∼70 mOsm caused “resting” [Ca2+]i as well as synaptically or directly stimulated transient increases of calcium activity (Δ[Ca2+]i) to transiently decrease and then to increase. In dissociated cells, lowering πo by ∼70 mOsm caused [Ca2+]i to almost double on average from 83 to 155 nM. The increase of [Ca2+]i was not significantly correlated with hypotonic cell swelling. Isoosmotic (mannitol- or sucrose-substituted) lowering of [NaCl]o, which did not cause cell swelling, also raised [Ca2+]i. Substituting NaCl with choline-Cl or Na-methyl-sulfate did not affect [Ca2+]i. In neurons bathed in calcium-free medium, lowering πo caused a milder increase of [Ca2+]i, which was correlated with cell swelling, but in the absence of external Ca2+, isotonic lowering of [NaCl]o triggered only a brief, transient response. We conclude that decrease of extracellular ionic strength (i.e., in both low πo and low [NaCl]o) causes a net influx of Ca2+ from the extracellular medium whereas cell swelling, or the increase in membrane tension, is a signal for the release of Ca2+ from intracellular stores.

scholarly journals Hippocampal neurons in direct contact with astrocytes exposed to amyloid β25-35 exhibit reduced excitatory synaptic transmission

IBRO Reports ◽  
2019 ◽  
Vol 7 ◽  
pp. 34-41 ◽  
Author(s):  
Kohei Oyabu ◽  
Hiroki Kiyota ◽  
Kaori Kubota ◽  
Takuya Watanabe ◽  
Shutaro Katsurabayashi ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Hippocampal Neurons ◽  
Direct Contact ◽  
Excitatory Synaptic Transmission

scholarly journals MmTX1 and MmTX2 from coral snake venom potently modulate GABAA receptor activity

2015 ◽  
Vol 112 (8) ◽  
pp. E891-E900 ◽  
Author(s):  
Jean-Pierre Rosso ◽  
Jürgen R. Schwarz ◽  
Marcelo Diaz-Bustamante ◽  
Brigitte Céard ◽  
José M. Gutiérrez ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Synaptic Transmission ◽  
Snake Venom ◽  
Hippocampal Neurons ◽  
Hippocampal Neuron ◽  
Costa Rican ◽  
Coral Snake ◽  
Receptor Sensitivity ◽  
Common Receptor ◽  
Receptor Family

GABAA receptors shape synaptic transmission by modulating Cl− conductance across the cell membrane. Remarkably, animal toxins that specifically target GABAA receptors have not been identified. Here, we report the discovery of micrurotoxin1 (MmTX1) and MmTX2, two toxins present in Costa Rican coral snake venom that tightly bind to GABAA receptors at subnanomolar concentrations. Studies with recombinant and synthetic toxin variants on hippocampal neurons and cells expressing common receptor compositions suggest that MmTX1 and MmTX2 allosterically increase GABAA receptor susceptibility to agonist, thereby potentiating receptor opening as well as desensitization, possibly by interacting with the α+/β− interface. Moreover, hippocampal neuron excitability measurements reveal toxin-induced transitory network inhibition, followed by an increase in spontaneous activity. In concert, toxin injections into mouse brain result in reduced basal activity between intense seizures. Altogether, we characterized two animal toxins that enhance GABAA receptor sensitivity to agonist, thereby establishing a previously unidentified class of tools to study this receptor family.

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