P3-432: Nanomolar concentrations of β-amyloid aggregates reduce spontaneous synaptic activity in hippocampal neurons

The N-methyl-d-aspartate (NMDA) receptor has been implicated in the formation of synaptic connections. To investigate the role of the ε2 (NR2B) NMDA receptor subunit, which is prominently expressed during early development, we used neurons from mice lacking this subunit. Although ε2−/− mice die soon after birth, we examined whether NMDA receptor targeting to the postsynaptic membrane was dependent on the ε2 subunit by rescuing hippocampal neurons from these mice and studying them in autaptic cultures. In voltage-clamp recordings, excitatory postsynaptic currents (EPSCs) from ε2−/− neurons expressed an NMDA receptor–mediated EPSC that was apparent as soon as synaptic activity developed. However, compared with wild-type neurons, NMDA receptor–mediated EPSC deactivation kinetics were much faster and were less sensitive to glycine, but were blocked by Mg2+ or AP5. Whole cell currents from ε2−/− neurons were also more sensitive to block by low concentrations of Zn2+ and much less sensitive to the ε2-specific antagonist ifenprodil than wild-type currents. The rapid NMDA receptor–mediated EPSC deactivation kinetics and the pharmacological profile from ε2−/−neurons are consistent with the expression of ζ1/ε1 diheteromeric receptors in excitatory hippocampal neurons from mice lacking the ε2 subunit. Thus ε1 can substitute for the ε2 subunit at synapses and ε2 is not required for targeting of NMDA receptors to the postsynaptic membrane.

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A Simple Depletion Model of the Readily Releasable Pool of Synaptic Vesicles Cannot Account for Paired-Pulse Depression

Journal of Neurophysiology ◽

10.1152/jn.00554.2006 ◽

2007 ◽

Vol 97 (1) ◽

pp. 948-950 ◽

Cited By ~ 10

Author(s):

Jane M. Sullivan

Keyword(s):

Synaptic Vesicles ◽

Hippocampal Neurons ◽

Synaptic Activity ◽

Excitatory Synapses ◽

Short Term ◽

Paired Pulse ◽

Short Term Plasticity ◽

Releasable Pool ◽

Readily Releasable Pool ◽

Paired Pulse Depression

Paired-pulse depression (PPD) is a form of short-term plasticity that plays a central role in processing of synaptic activity and is manifest as a decrease in the size of the response to the second of two closely timed stimuli. Despite mounting evidence to the contrary, PPD is still commonly thought to reflect depletion of the pool of synaptic vesicles available for release in response to the second stimulus. Here it is shown that PPD cannot be accounted for by depletion at excitatory synapses made by hippocampal neurons because PPD is unaffected by changes in the fraction of the readily releasable pool (RRP) released by the first of a pair of pulses.

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Fine Tuning of Intracellular Ca2+ Content by Pharmacological Agents – A Strategy to Prevent Synapse Loss in Alzheimer Disease Hippocampal Neurons

Current Alzheimer Research ◽

10.2174/1567205018666210119145735 ◽

2021 ◽

Vol 17 (12) ◽

pp. 1065-1071

Author(s):

Elena Popugaeva

Keyword(s):

Alzheimer Disease ◽

Calcium Channels ◽

Hippocampal Neurons ◽

Long Term Potentiation ◽

Fine Tuning ◽

Dominant Form ◽

Pharmacological Agents ◽

Chemical Structures ◽

Synapse Loss ◽

Β Amyloid

: Alzheimer disease is the dominant form of elderly dementia. Today all clinical trials that target β-amyloid have failed to indicate that β-amyloid may not be a causative agent in AD pathogenesis. Thus there is a need to search for alternative ways to treat AD patients. : Neuronal store-operated calcium entry is a fine-tuning mechanism that regulates intracellular Ca2+ content. Recent evidence suggests that store-operated calcium channels may be targeted with pharmacological agents in order to prevent synapse loss, recover long-term potentiation and change behavior. : Current mini-review discusses basic chemical structures that modulate intracellular calcium dysbalance via targeting store-operated calcium channels and their applicability as anti-AD pharmacological agents.

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Gut dysbiosis contributes to amyloid pathology, associated with C/EBPβ/AEP signaling activation in Alzheimer’s disease mouse model

Science Advances ◽

10.1126/sciadv.aba0466 ◽

2020 ◽

Vol 6 (31) ◽

pp. eaba0466 ◽

Cited By ~ 2

Author(s):

Chun Chen ◽

Eun Hee Ahn ◽

Seong Su Kang ◽

Xia Liu ◽

Ashfaqul Alam ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gut Dysbiosis ◽

Enhancer Binding Protein ◽

Amyloid Aggregates ◽

Gut Leakage ◽

Β Amyloid ◽

5Xfad Mice ◽

Signaling Activation ◽

The Brain

The gut-brain axis is bidirectional, and gut microbiota influence brain disorders including Alzheimer’s disease (AD). CCAAT/enhancer binding protein β/asparagine endopeptidase (C/EBPβ/AEP) signaling spatiotemporally mediates AD pathologies in the brain via cleaving both β-amyloid precursor protein and Tau. We show that gut dysbiosis occurs in 5xFAD mice, and is associated with escalation of the C/EBPβ/AEP pathway in the gut with age. Unlike that of aged wild-type mice, the microbiota of aged 3xTg mice accelerate AD pathology in young 3xTg mice, accompanied by active C/EBPβ/AEP signaling in the brain. Antibiotic treatment diminishes this signaling and attenuates amyloidogenic processes in 5xFAD, improving cognitive functions. The prebiotic R13 inhibits this pathway and suppresses amyloid aggregates in the gut. R13-induced Lactobacillus salivarius antagonizes the C/EBPβ/AEP axis, mitigating gut leakage and oxidative stress. Our findings support the hypothesis that C/EBPβ/AEP signaling is activated by gut dysbiosis, implicated in AD pathologies in the gut.

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PD98059 Prevents Neurite Degeneration Induced by Fibrillar β-Amyloid in Mature Hippocampal Neurons

Journal of Neurochemistry ◽

10.1046/j.1471-4159.2000.0740125.x ◽

2001 ◽

Vol 74 (1) ◽

pp. 125-133 ◽

Cited By ~ 100

Author(s):

Mark Rapoport ◽

Adriana Ferreira

Keyword(s):

Hippocampal Neurons ◽

Β Amyloid ◽

Neurite Degeneration

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Neuron-based high-content assay and screen for CNS active mitotherapeutics

Science Advances ◽

10.1126/sciadv.aaw8702 ◽

2020 ◽

Vol 6 (2) ◽

pp. eaaw8702 ◽

Cited By ~ 2

Author(s):

Boglarka H. Varkuti ◽

Miklos Kepiro ◽

Ze Liu ◽

Kyle Vick ◽

Yosef Avchalumov ◽

...

Keyword(s):

Small Molecule ◽

Hippocampal Neurons ◽

Mitochondrial Dynamics ◽

Synaptic Activity ◽

Glutamate Toxicity ◽

Primary Neurons ◽

Screening Assay ◽

Dynamics And Function ◽

Small Molecule Modulators ◽

And Function

Impaired mitochondrial dynamics and function are hallmarks of many neurological and psychiatric disorders, but direct screens for mitotherapeutics using neurons have not been reported. We developed a multiplexed and high-content screening assay using primary neurons and identified 67 small-molecule modulators of neuronal mitostasis (MnMs). Most MnMs that increased mitochondrial content, length, and/or health also increased mitochondrial function without altering neurite outgrowth. A subset of MnMs protected mitochondria in primary neurons from Aβ(1–42) toxicity, glutamate toxicity, and increased oxidative stress. Some MnMs were shown to directly target mitochondria. The top MnM also increased the synaptic activity of hippocampal neurons and proved to be potent in vivo, increasing the respiration rate of brain mitochondria after administering the compound to mice. Our results offer a platform that directly queries mitostasis processes in neurons, a collection of small-molecule modulators of mitochondrial dynamics and function, and candidate molecules for mitotherapeutics.

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