scholarly journals Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1871
Author(s):  
Märta Dahlström ◽  
Nather Madjid ◽  
Gunnar Nordvall ◽  
Magnus M. Halldin ◽  
Erika Vazquez-Juarez ◽  
...  
Keyword(s):  
Cognitive Dysfunction ◽  
Long Term Potentiation ◽  
Dependent Manner ◽  
Allosteric Modulators ◽  
Neurotrophin Receptors ◽  
Trk Receptors ◽  
Term Potentiation ◽  
Positive Allosteric Modulators ◽  
Old Mice

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and results in severe neurodegeneration and progressive cognitive decline. Neurotrophins are growth factors involved in the development and survival of neurons, but also in underlying mechanisms for memory formation such as hippocampal long-term potentiation. Our aim was to identify small molecules with stimulatory effects on the signaling of two neurotrophins, the nerve growth factor (NGF) and the brain derived neurotrophic factor (BDNF). To identify molecules that could potentiate neurotrophin signaling, 25,000 molecules were screened, which led to the identification of the triazinetrione derivatives ACD855 (Ponazuril) and later on ACD856, as positive allosteric modulators of tropomyosin related kinase (Trk) receptors. ACD855 or ACD856 potentiated the cellular signaling of the neurotrophin receptors with EC50 values of 1.9 and 3.2 or 0.38 and 0.30 µM, respectively, for TrkA or TrkB. ACD855 increased acetylcholine levels in the hippocampus by 40% and facilitated long term potentiation in rat brain slices. The compounds acted as cognitive enhancers in a TrkB-dependent manner in several different behavioral models. Finally, the age-induced cognitive dysfunction in 18-month-old mice could be restored to the same level as found in 2-month-old mice after a single treatment of ACD856. We have identified a novel mechanism to modulate the activity of the Trk-receptors. The identification of the positive allosteric modulators of the Trk-receptors might have implications for the treatment of Alzheimer’s diseases and other diseases characterized by cognitive impairment.

scholarly journals mGlu5 Positive Allosteric Modulators Facilitate Long-Term Potentiation via Disinhibition Mediated by mGlu5-Endocannabinoid Signaling

2019 ◽  
Vol 2 (3) ◽  
pp. 198-209 ◽  
Author(s):  
Zixiu Xiang ◽  
Xiaohui Lv ◽  
James Maksymetz ◽  
Branden J. Stansley ◽  
Ayan Ghoshal ◽  
...  
Keyword(s):  
Long Term Potentiation ◽  
Allosteric Modulators ◽  
Term Potentiation ◽  
Positive Allosteric Modulators

Long-Term Moderate Exercise Rescues Age-Related Decline in Hippocampal Neuronal Complexity and Memory

Gerontology ◽  
2018 ◽  
Vol 64 (6) ◽  
pp. 551-561 ◽  
Author(s):  
Sheng-Feng Tsai ◽  
Nai-Wen Ku ◽  
Tzu-Feng Wang ◽  
Yan-Hsiang Yang ◽  
Yao-Hsiang Shih ◽  
...  
Keyword(s):  
Learning And Memory ◽  
Memory Function ◽  
Long Term Potentiation ◽  
Treadmill Running ◽  
Moderate Intensity ◽  
Middle Aged ◽  
Ca1 Neurons ◽  
Term Potentiation ◽  
Old Mice

Background: Aging impairs hippocampal neuroplasticity and hippocampus-related learning and memory. In contrast, exercise training is known to improve hippocampal neuronal function. However, whether exercise is capable of restoring memory function in old animals is less clear. Objective: Here, we investigated the effects of exercise on the hippocampal neuroplasticity and memory functions during aging. Methods: Young (3 months), middle-aged (9–12 months), and old (18 months) mice underwent moderate-intensity treadmill running training for 6 weeks, and their hippocampus-related learning and memory, and the plasticity of their CA1 neurons was evaluated. Results: The memory performance (Morris water maze and novel object recognition tests), and dendritic complexity (branch and length) and spine density of their hippocampal CA1 neurons decreased as their age increased. The induction and maintenance of high-frequency stimulation-induced long-term potentiation in the CA1 area and the expressions of neuroplasticity-related proteins were not affected by age. Treadmill running increased CA1 neuron long-term potentiation and dendritic complexity in all three age groups, and it restored the learning and memory ability in middle-aged and old mice. Furthermore, treadmill running upregulated the hippocampal expressions of brain-derived neurotrophic factor and monocarboxylate transporter-4 in middle-aged mice, glutamine synthetase in old mice, and full-length TrkB in middle-aged and old mice. Conclusion: The hippocampus-related memory function declines from middle age, but long-term moderate-intensity running effectively increased hippocampal neuroplasticity and memory in mice of different ages, even when the memory impairment had progressed to an advanced stage. Thus, long-term, moderate intensity exercise training might be a way of delaying and treating aging-related memory decline.

Long-term potentiation of nicotinic transmission by a heterosynaptic mechanism in the stellate ganglion of the cat

1991 ◽  
Vol 65 (3) ◽  
pp. 639-647 ◽  
Author(s):  
M. Bachoo ◽  
C. Polosa
Keyword(s):  
Time Course ◽  
Stellate Ganglion ◽  
Compound Action Potential ◽  
Long Term Potentiation ◽  
Dependent Manner ◽  
Similar Time ◽  
Small Magnitude ◽  
Test Input ◽  
Term Potentiation

1. In the anesthetized, scopolamine-treated cat, the compound action potential (CAP) evoked by a single supramaximal shock to the third thoracic white ramus (T3WR) was recorded in the inferior cardiac nerve (ICN). The CAP was depressed in a dose-dependent manner by the intravenous administration of the nicotinic antagonist hexamethonium (C6). 2. During steady intravenous infusion of C6, which reduced the amplitude of the CAP by 80-90%, a short train of stimuli (few seconds, 10-40 Hz) to the sympathetic trunk just below T4WR potentiated the CAP for periods of tens of minutes to 1-2 h (heterosynaptic long-term potentiation, LTP). An LTP of similar time course was obtained when both train and single shock were applied to T3WR (homosynaptic LTP). Magnitude and duration of the heterosynaptic LTP were dependent on number, frequency, and intensity of the stimuli. No LTP was produced by a train to the ICN. Heterosynaptic LTP was also observed in the absence of C6. Because of the limited subliminal fringe of the test input under this condition, the LTP was of small magnitude. Heterosynaptic LTP also of the heart rate (HR) response to a test stimulus was observed after a conditioning train. 3. The conditioning train produced a displacement to the right of the dose-response curve for C6. The intravenous dose of C6 required for 50% attenuation of the test CAP increased from 0.84 +/- 0.15 (SE) mg/kg pretrain to 2.56 +/- 0.46 mg/kg posttrain (n = 5, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Long-Term Potentiation in the Hippocampal CA1 Region Does Not Require Insertion and Activation of GluR2-Lacking AMPA Receptors

2007 ◽  
Vol 98 (4) ◽  
pp. 2488-2492 ◽  
Author(s):  
Erin E. Gray ◽  
Ann E. Fink ◽  
Joshua Sariñana ◽  
Bryce Vissel ◽  
Thomas J. O'Dell
Keyword(s):  
Glutamate Receptor ◽  
Ampa Receptors ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
Ca1 Region ◽  
Hippocampal Ca1 Region ◽  
Term Potentiation ◽  
Hippocampal Ca1 ◽  
Old Mice

Activity-dependent insertion of AMPA-type glutamate receptors is thought to underlie long-term potentiation (LTP) at Schaffer collateral fiber synapses on pyramidal cells in the hippocampal CA1 region. Although it is widely accepted that the AMPA receptors at these synapses contain glutamate receptor type 2 (GluR2) subunits, recent findings suggest that LTP in hippocampal slices obtained from 2- to 3-wk-old rodents is dependent on the transient postsynaptic insertion and activation of Ca2+-permeable, GluR2-lacking AMPA receptors. Here we examined whether LTP in slices prepared from adult animals exhibits similar properties. In contrast to previously reported findings, pausing synaptic stimulation for as long as 30 min post LTP induction had no effect on LTP maintenance in slices from 2- to 3-mo-old mice. LTP was also not disrupted by postinduction application of a selective blocker of GluR2-lacking AMPA receptors or the broad-spectrum glutamate receptor antagonist kynurenate. Although these results suggest that the role of GluR2-lacking AMPA receptors in LTP might be regulated during postnatal development, LTP in slices obtained from 15- to 21-day-old mice also did not require postinduction synaptic stimulation or activation of GluR2-lacking AMPA receptors. Thus the insertion and activation of GluR2-lacking AMPA receptors do not appear to be fundamental processes involved in LTP at excitatory synapses in the hippocampal CA1 region.

Blockade of Long-Term Potentiation by β-Amyloid Peptides in the CA1 Region of the Rat Hippocampus In Vivo

2001 ◽  
Vol 85 (2) ◽  
pp. 708-713 ◽  
Author(s):  
Darragh B. Freir ◽  
Christian Holscher ◽  
Caroline E. Herron
Keyword(s):  
Long Term Potentiation ◽  
Amyloid Peptide ◽  
Excitatory Postsynaptic Potential ◽  
Dependent Manner ◽  
Aβ Peptides ◽  
Ca1 Region ◽  
Term Potentiation ◽  
Β Amyloid

The effect of intracerebroventricular (icv) injections of β-amyloid peptide fragments Aβ[15–25], Aβ[25–35], and Aβ[35–25] were examined on synaptic transmission and long-term potentiation (LTP) in the hippocampal CA1 region in vivo. Rats were anesthetized using urethan, and changes in synaptic efficacy were determined from the slope of the excitatory postsynaptic potential (EPSP). Baseline synaptic responses were monitored for 30 min prior to icv injection of Aβ peptides or vehicle. High-frequency stimulation (HFS) to induce LTP was applied to the Schaffer-collateral pathway 5 min or 1 h following the icv injection. HFS comprised 3 episodes of 10 stimuli at 200 Hz, 10 times, applied at 30-s intervals. Normal LTP measured 30 min following HFS, was produced following icv injection of vehicle (191 ± 17%, mean ± SE, n = 6) or Aβ[15–25; 100 nmol] (177 ± 6%, n = 6) 1 h prior to HFS. LTP was, however, markedly reduced by Aβ[25–35; 10 nmol] (129 ± 9%, n = 6, P < 0.001) and blocked by Aβ[25–35; 100 nmol] (99 ± 6%, n = 6, P < 0.001). Injection of the reverse peptide, Aβ[35–25], also impaired LTP at concentrations of 10 nmol (136 ± 3%, n = 6, P < 0.01) and 100 nmol (144 ± 7, n = 8, P < 0.05). Using a different protocol, HFS was delivered 5 min following Aβ injections, and LTP was measured 1 h post HFS. Stable LTP was produced in the control group (188 ± 15%, n = 7) and blocked by Aβ[25–35, 100 nmol] (108 ± 15%, n = 6, P < 0.001). A lower dose of Aβ[25–35; 10 nmol] did not significantly impair LTP (176 ± 30%, n = 4). The Aβ-peptides tested were also shown to have no significant effect on paired pulse facilitation (interstimulus interval of 50 ms), suggesting that neither presynaptic transmitter release or activity of interneurons in vivo are affected. The effects of Aβ on LTP are therefore likely to be mediated via a postsynaptic mechanism. This in vivo model of LTP is extremely sensitive to Aβ-peptides that can impair LTP in a time- ([25–35]) and concentration-dependent manner ([25–35] and [35–25]). These effects of Aβ-peptides may then contribute to the cognitive deficits associated with Alzheimer's disease.

scholarly journals The AMPA receptor positive allosteric modulator S 47445 rescues in vivo CA3-CA1 long-term potentiation and structural synaptic changes in old mice

2017 ◽  
Vol 123 ◽  
pp. 395-409 ◽  
Author(s):  
Albert Giralt ◽  
María Ángeles Gómez-Climent ◽  
Rafael Alcalá ◽  
Sylvie Bretin ◽  
Daniel Bertrand ◽  
...  
Keyword(s):  
Ampa Receptor ◽  
Long Term Potentiation ◽  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
Term Potentiation ◽  
Synaptic Changes ◽  
Old Mice

scholarly journals Glucocorticoid receptor-mediated amygdalar metaplasticity underlies adaptive modulation of fear memory by stress

2017 ◽  
Author(s):  
Ran Inoue ◽  
Kareem Abdou ◽  
Ayumi Hayashi-Tanaka ◽  
Shin-ichi Muramatsu ◽  
Kaori Mino ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Fear Conditioning ◽  
Adaptive Modulation ◽  
Long Term Potentiation ◽  
Fear Memory ◽  
Suppressive Effect ◽  
Dependent Manner ◽  
Term Potentiation ◽  
Lateral Nucleus

AbstractGlucocorticoid receptor (GR) is crucial for signaling mediated by stress-induced high levels of glucocorticoids. The lateral nucleus of the amygdala (LA) is a key structure underlying auditory-cued fear conditioning. Here, we demonstrate that genetic disruption of GR in the LA (LAGRKO) resulted in an auditory-cued fear memory deficit for strengthened conditioning. Furthermore, the suppressive effect of a single restraint stress (RS) prior to conditioning on auditory-cued fear memory in floxed GR (control) mice was abolished in LAGRKO mice. Optogenetic induction of long-term depression (LTD) at auditory inputs to the LA reduced auditory-cued fear memory in RS-exposed LAGRKO mice, and in contrast, optogenetic induction of long-term potentiation (LTP) increased auditory-cued fear memory in RS-exposed floxed GR mice. These findings suggest that prior stress suppresses fear conditioning-induced LTP at auditory inputs to the LA in a GR-dependent manner, thereby protecting animals from encoding excessive cued fear memory under stress conditions.

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