scholarly journals Chemical Stimulation of Rodent and Human Cortical Synaptosomes: Implications in Neurodegeneration

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1174
Author(s):  
Faraz Ahmad ◽  
Yu Jing ◽  
Albert Lladó ◽  
Ping Liu
Keyword(s):  
Ex Vivo ◽  
Long Term Potentiation ◽  
Chemical Stimulation ◽  
Actin Dynamics ◽  
Synaptic Physiology ◽  
Brain Functions ◽  
Chemically Induced ◽  
Term Potentiation ◽  
Early Onset Alzheimer’S Disease ◽  
First Time

Synaptic plasticity events, including long-term potentiation (LTP), are often regarded as correlates of brain functions of memory and cognition. One of the central players in these plasticity-related phenomena is the α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor (AMPAR). Increased levels of AMPARs on postsynaptic membranes thus constitute a biochemical measure of LTP. Isolated synaptic terminals (synaptosomes) are an excellent ex vivo tool to monitor synaptic physiology in healthy and diseased brains, particularly in human research. We herein describe three protocols for chemically-induced LTP (cLTP) in synaptosomes from both rodent and human brain tissues. Two of these chemical stimulation protocols are described for the first time in synaptosomes. A pharmacological block of synaptosomal actin dynamics confirmed the efficiency of the cLTP protocols. Furthermore, the study prototypically evaluated the deficiency of cLTP in cortical synaptosomes obtained from human cases of early-onset Alzheimer’s disease (EOAD) and frontotemporal lobar degeneration (FLTD), as well as an animal model that mimics FLTD.

scholarly journals Aη-α and Aη-β peptides impair LTP ex vivo within the low nanomolar range and impact neuronal activity in vivo

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Maria Mensch ◽  
Jade Dunot ◽  
Sandy M. Yishan ◽  
Samuel S. Harris ◽  
Aline Blistein ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Ex Vivo ◽  
Long Term Potentiation ◽  
Network Activity ◽  
Strongly Correlated ◽  
App Processing ◽  
Term Potentiation ◽  
Hippocampal Network

Abstract Background Amyloid precursor protein (APP) processing is central to Alzheimer’s disease (AD) etiology. As early cognitive alterations in AD are strongly correlated to abnormal information processing due to increasing synaptic impairment, it is crucial to characterize how peptides generated through APP cleavage modulate synapse function. We previously described a novel APP processing pathway producing η-secretase-derived peptides (Aη) and revealed that Aη–α, the longest form of Aη produced by η-secretase and α-secretase cleavage, impaired hippocampal long-term potentiation (LTP) ex vivo and neuronal activity in vivo. Methods With the intention of going beyond this initial observation, we performed a comprehensive analysis to further characterize the effects of both Aη-α and the shorter Aη-β peptide on hippocampus function using ex vivo field electrophysiology, in vivo multiphoton calcium imaging, and in vivo electrophysiology. Results We demonstrate that both synthetic peptides acutely impair LTP at low nanomolar concentrations ex vivo and reveal the N-terminus to be a primary site of activity. We further show that Aη-β, like Aη–α, inhibits neuronal activity in vivo and provide confirmation of LTP impairment by Aη–α in vivo. Conclusions These results provide novel insights into the functional role of the recently discovered η-secretase-derived products and suggest that Aη peptides represent important, pathophysiologically relevant, modulators of hippocampal network activity, with profound implications for APP-targeting therapeutic strategies in AD.

scholarly journals Cognitive functions and underlying parameters of human brain physiology are associated with chronotype

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mohammad Ali Salehinejad ◽  
Miles Wischnewski ◽  
Elham Ghanavati ◽  
Mohsen Mosayebi-Samani ◽  
Min-Fang Kuo ◽  
...  
Keyword(s):  
Motor Learning ◽  
Human Brain ◽  
Cognitive Functions ◽  
Cortical Excitability ◽  
Long Term Potentiation ◽  
Cortical Inhibition ◽  
Memory And Attention ◽  
Brain Physiology ◽  
Brain Functions ◽  
Term Potentiation

AbstractCircadian rhythms have natural relative variations among humans known as chronotype. Chronotype or being a morning or evening person, has a specific physiological, behavioural, and also genetic manifestation. Whether and how chronotype modulates human brain physiology and cognition is, however, not well understood. Here we examine how cortical excitability, neuroplasticity, and cognition are associated with chronotype in early and late chronotype individuals. We monitor motor cortical excitability, brain stimulation-induced neuroplasticity, and examine motor learning and cognitive functions at circadian-preferred and non-preferred times of day in 32 individuals. Motor learning and cognitive performance (working memory, and attention) along with their electrophysiological components are significantly enhanced at the circadian-preferred, compared to the non-preferred time. This outperformance is associated with enhanced cortical excitability (prominent cortical facilitation, diminished cortical inhibition), and long-term potentiation/depression-like plasticity. Our data show convergent findings of how chronotype can modulate human brain functions from basic physiological mechanisms to behaviour and higher-order cognition.

scholarly journals Phosphorylation of the AMPAR-TARP Complex in Synaptic Plasticity

Proteomes ◽  
2018 ◽  
Vol 6 (4) ◽  
pp. 40 ◽  
Author(s):  
Joongkyu Park
Keyword(s):  
Synaptic Plasticity ◽  
Drug Addiction ◽  
Ampa Receptor ◽  
Long Term Potentiation ◽  
Synaptic Activity ◽  
Regulatory Proteins ◽  
Cellular Models ◽  
Brain Functions ◽  
Term Potentiation

Synaptic plasticity has been considered a key mechanism underlying many brain functions including learning, memory, and drug addiction. An increase or decrease in synaptic activity of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) complex mediates the phenomena as shown in the cellular models of synaptic plasticity, long-term potentiation (LTP), and depression (LTD). In particular, protein phosphorylation shares the spotlight in expressing the synaptic plasticity. This review summarizes the studies on phosphorylation of the AMPAR pore-forming subunits and auxiliary proteins including transmembrane AMPA receptor regulatory proteins (TARPs) and discusses its role in synaptic plasticity.

Estrogenic Regulation of Synaptic Actin Proteins and Plasticity

2020 ◽  
pp. 69-82
Author(s):  
Enikö A. Kramár
Keyword(s):  
Synaptic Plasticity ◽  
Long Term Potentiation ◽  
Synaptic Strength ◽  
Adult Brain ◽  
Actin Dynamics ◽  
Signaling Cascade ◽  
Term Potentiation ◽  
Estrogenic Regulation ◽  
Estradiol Levels

Estrogens are rapid and potent facilitators of synaptic plasticity in the adult brain; however, the steps that link estrogens to factors that regulate synaptic strength remain unclear. The present chapter will first review the acute effects of 17β‎-estradiol on synaptic transmission and long-term potentiation (LTP). It will then describe a synaptic model used to study the substrates of LTP and provide evidence for the ability of estradiol to rapidly engage a selective actin signaling cascade associated with the consolidation of LTP. Finally, it will be shown that chronic reductions in estradiol levels disrupt LTP and actin dynamics but can be reversed by acute infusions of the hormone. It is concluded here that estradiol can promote learning-related plasticity by modifying the synaptic cytoskeleton.

scholarly journals Chemical LTD, but not LTP, induces transient accumulation of gelsolin in dendritic spines

2019 ◽  
Vol 400 (9) ◽  
pp. 1129-1139 ◽  
Author(s):  
Iryna Hlushchenko ◽  
Pirta Hotulainen
Keyword(s):  
Synaptic Plasticity ◽  
Dendritic Spines ◽  
Hippocampal Neurons ◽  
Long Term Potentiation ◽  
Excitatory Synapses ◽  
Signal Molecule ◽  
Brain Functions ◽  
Dendritic Shaft ◽  
Term Potentiation

Abstract Synaptic plasticity underlies central brain functions, such as learning. Ca2+ signaling is involved in both strengthening and weakening of synapses, but it is still unclear how one signal molecule can induce two opposite outcomes. By identifying molecules, which can distinguish between signaling leading to weakening or strengthening, we can improve our understanding of how synaptic plasticity is regulated. Here, we tested gelsolin’s response to the induction of chemical long-term potentiation (cLTP) or long-term depression (cLTD) in cultured rat hippocampal neurons. We show that gelsolin relocates from the dendritic shaft to dendritic spines upon cLTD induction while it did not show any relocalization upon cLTP induction. Dendritic spines are small actin-rich protrusions on dendrites, where LTD/LTP-responsive excitatory synapses are located. We propose that the LTD-induced modest – but relatively long-lasting – elevation of Ca2+ concentration increases the affinity of gelsolin to F-actin. As F-actin is enriched in dendritic spines, it is probable that increased affinity to F-actin induces the relocalization of gelsolin.

Effect of tolbutamide on tetraethylammonium-induced postsynaptic zinc signals at hippocampal mossy fiber-CA3 synapses

2017 ◽  
Vol 95 (9) ◽  
pp. 1058-1063 ◽  
Author(s):  
Fatima C. Bastos ◽  
Vanessa N. Corceiro ◽  
Sandra A. Lopes ◽  
José G. de Almeida ◽  
Carlos M. Matias ◽  
...  
Keyword(s):  
Mossy Fiber ◽  
Mossy Fibers ◽  
Pyramidal Cells ◽  
Long Term Potentiation ◽  
Chemical Stimulation ◽  
Term Potentiation ◽  
Voltage Dependent ◽  
Zinc Release ◽  
Ca3 Pyramidal Cells

The application of tetraethylammonium (TEA), a blocker of voltage-dependent potassium channels, can induce long-term potentiation (LTP) in the synaptic systems CA3–CA1 and mossy fiber-CA3 pyramidal cells of the hippocampus. In the mossy fibers, the depolarization evoked by extracellular TEA induces a large amount of glutamate and also of zinc release. It is considered that zinc has a neuromodulatory role at the mossy fiber synapses, which can, at least in part, be due to the activation of presynaptic ATP-dependent potassium (KATP) channels. The aim of this work was to study properties of TEA-induced zinc signals, detected at the mossy fiber region, using the permeant form of the zinc indicator Newport Green. The application of TEA caused a depression of those signals that was partially blocked by the KATP channel inhibitor tolbutamide. After the removal of TEA, the signals usually increased to a level above baseline. These results are in agreement with the idea that intense zinc release during strong synaptic events triggers a negative feedback action. The zinc depression, caused by the LTP-evoking chemical stimulation, turns into potentiation after TEA washout, suggesting the existence of a correspondence between the observed zinc potentiation and TEA-evoked mossy fiber LTP.

scholarly journals Delayed inhibition of tonic inhibition enhances functional recovery following experimental ischemic stroke

2017 ◽  
Vol 39 (6) ◽  
pp. 1005-1014 ◽  
Author(s):  
James E Orfila ◽  
Himmat Grewal ◽  
Robert M Dietz ◽  
Frank Strnad ◽  
Takeru Shimizu ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Functional Recovery ◽  
Ex Vivo ◽  
Long Term Potentiation ◽  
Artery Occlusion ◽  
Memory Impairments ◽  
Time Points ◽  
Term Potentiation ◽  
Cerebral Artery Occlusion

The current study focuses on the ability to improve cognitive function after stroke with interventions administered at delayed/chronic time points. In light of recent studies demonstrating delayed GABA antagonists improve motor function, we utilized electrophysiology, biochemistry and neurobehavioral methods to investigate the role of α5 GABAA receptors on hippocampal plasticity and functional recovery following ischemic stroke. Male C57Bl/6 mice were exposed to 45 min transient middle cerebral artery occlusion and analysis of synaptic and functional deficits performed 7 or 30 days after recovery. Our findings indicate that hippocampal long-term potentiation (LTP) is impaired 7 days after stroke and remain impaired for at least 30 days. We demonstrate that ex vivo administration of L655,708 reversed ischemia-induced plasticity deficits and importantly, in vivo administration at delayed time-points reversed stroke-induced memory deficits. Western blot analysis of hippocampal tissue reveals proteins responsible for GABA synthesis are upregulated (GAD65/67 and MAOB), increasing GABA in hippocampal interneurons 30 days after stroke. Thus, our data indicate that both synaptic plasticity and memory impairments observed after stroke are caused by excessive tonic GABA activity, making inhibition of specific GABA activity at delayed timepoints a potential therapeutic approach to improve functional recovery and reverse cognitive impairments after stroke.

scholarly journals Disinhibition-assisted LTP in the prefrontal-amygdala pathway via suppression of somatostatin-expressing interneurons

2019 ◽  
Author(s):  
Wataru Ito ◽  
Brendon Fusco ◽  
Alexei Morozov
Keyword(s):  
Basolateral Amygdala ◽  
Ex Vivo ◽  
Low Frequency ◽  
Long Term Potentiation ◽  
Synaptic Strength ◽  
Neuronal Firing ◽  
High Frequency Stimulation ◽  
Term Potentiation ◽  
Frequency Stimulation

AbstractNatural brain adaptations often involve changes in synaptic strength. The artificial manipulations can help investigate the role of synaptic strength in a specific brain circuit not only in various physiological phenomena like correlated neuronal firing and oscillations but also in behaviors. High and low-frequency stimulation at presynaptic sites has been used widely to induce long-term potentiation (LTP) and depression (LTD), respectively. This approach is effective in many brain areas, but not in the basolateral amygdala (BLA), because the robust local GABAergic tone inside the BLA restricts synaptic plasticity. Here, we identified the subclass of GABAergic neurons that gate LTP in the BLA afferents from the dorsomedial prefrontal cortex (dmPFC). Chemogenetic suppression of somatostatin-positive interneurons (Sst-INs) enabled the ex vivo LTP by high-frequency stimulation of the afferent, but the suppression of parvalbumin-positive interneurons (PV-INs) did not. Moreover, optogenetic suppression of Sst-INs with Arch also enabled LTP of the dmPFC-BLA synapses both ex vivo and in vivo. These findings reveal that Sst-INs but not PV-INs gate LTP in the dmPFC-BLA pathway and provide a method for artificial synaptic facilitation in BLA.

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