Pharmacology of Ampakine Modulators: From AMPA Receptors to Synapses and Behavior

Ac, Arai; Kessler, Markus

doi:10.2174/138945007780618490

Cited by 186 publications

(164 citation statements)

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“…If so, then amplifying theta burst responses could allow TBS1 to induce LTP machinery in the high threshold cases. We tested this using a positive allosteric modulator of AMPA-type glutamate receptors (18,19) to increase the composite depolarization produced by TBS1 (Fig. 2C).…”

Section: Resultsmentioning

confidence: 99%

Synaptic evidence for the efficacy of spaced learning

Kramár¹,

Babayan²,

Gavin

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

157

189

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The superiority of spaced vs. massed training is a fundamental feature of learning. Here, we describe unanticipated timing rules for the production of long-term potentiation (LTP) in adult rat hippocampal slices that can account for one temporal segment of the spaced trials phenomenon. Successive bouts of naturalistic theta burst stimulation of field CA1 afferents markedly enhanced previously saturated LTP if spaced apart by 1 h or longer, but were without effect when shorter intervals were used. Analyses of Factin-enriched spines to identify potentiated synapses indicated that the added LTP obtained with delayed theta trains involved recruitment of synapses that were "missed" by the first stimulation bout. Single spine glutamate-uncaging experiments confirmed that less than half of the spines in adult hippocampus are primed to undergo plasticity under baseline conditions, suggesting that intrinsic variability among individual synapses imposes a repetitive presentation requirement for maximizing the percentage of potentiated connections. We propose that a combination of local diffusion from initially modified spines coupled with much later membrane insertion events dictate that the repetitions be widely spaced. Thus, the synaptic mechanisms described here provide a neurobiological explanation for one component of a poorly understood, ubiquitous aspect of learning.A n extensive body of experimental work indicates that periodic exposure to the same material results in better retention than a single "cramming" session. Although this distributed practice effect was first recognized in late 19th century (1-3), and has since been the subject of a very large psychological literature (4), the neurobiological processes that give rise to the phenomenon are poorly understood. Activity-dependent synaptic plasticity, and, in particular, long-term potentiation (LTP) of glutamatergic transmission, is thought to underlie rapid storage of new information (5, 6). Therefore, it is surprising that little experimental attention has been given to the possibility that specialized features of LTP may contribute to the spaced trials (distributed practice) effect. This likely reflects the lack of data indicating that the substrates of the potentiation effect include properties that are engaged, or enhanced, only by widely spaced stimulation episodes. Specifically, several types of studies point to the conclusion that the elaborate processes yielding fully developed LTP reach completion within 10-15 min (5, 7, 8); these findings do not include results suggestive of a delayed capacity for triggering additional changes to already potentiated synapses. There is considerable evidence for a later LTP stabilization step involving protein synthesis (9), but the effects of this on subsequent plasticity involve inputs other than those already expressing potentiation (10).Here, we describe a set of mechanisms and timing rules in hippocampus that result in widely spaced episodes of theta burst stimulation (TBS) generating a much greater degree of LT...

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Section: Resultsmentioning

confidence: 99%

Synaptic evidence for the efficacy of spaced learning

Kramár¹,

Babayan²,

Gavin

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

157

189

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“…decrease receptor desensitization or deactivation) [57,58]. AMPA receptor potentiating drugs increase the size of EPSPs, enhance LTP, enhance learning and memory, and increase BDNF [59,60].…”

Section: Potential Synaptogenic Targetsmentioning

confidence: 99%

A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists

Duman

2012

Phil. Trans. R. Soc. B

295

190

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Molecular and cellular studies have demonstrated opposing actions of stress and antidepressant treatment on the expression of neurotrophic factors, particularly brain-derived neurotrophic factor, in limbic structures of the brain. These changes in neurotrophic factor expression and function result in structural alterations, including regulation of neurogenesis, dendrite length and spine density in hippocampus and prefrontal cortex (PFC). The deleterious effects of stress could contribute to the reduced volume of these brain regions in depressed patients. Conversely, the actions of antidepressant treatment could be mediated in part by blocking or reversing the atrophy caused by stress and depression. Recent studies have identified a novel, rapid-acting antidepressant, ketamine, in treatment-resistant depressed patients that addresses the limitations of currently available agents (i.e. delayed onset of action and low response rates). We have found that ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, causes a rapid induction of synaptogenesis and spine formation in the PFC via stimulation of the mammalian target of the rapamycin signalling pathway and increased synthesis of synaptic proteins. These effects of ketamine rapidly reverse the atrophy of PFC neurons caused by chronic stress and correspond to rapid behavioural actions of ketamine in models of depression. Characterization of a novel signalling pathway also identifies new cellular targets that could result in rapid and efficacious antidepressant actions without the side effects of ketamine.

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“…There were reports indicating that endogenous BDNF level could be elevated by short-term administration of specific compounds, for example, the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid AMPA receptor modulator ampakine [58] . Ampakines are a group of small molecules that can delay deactivation and reduce desensitization of AMPA type glutamate receptors and thereby increase the size and duration of ligand-gated current flow, enhancing glutamate transmission [59,60] . In addition, previous studies showed that regular ampakine administration would increase the expression of BDNF.…”

Section: Future Directionsmentioning

confidence: 99%

Chronic intermittent hypoxia-induced deficits in synaptic plasticity and neurocognitive functions: a role for brain-derived neurotrophic factor

Xie

Yung

2012

Acta Pharmacol Sin

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Obstructive sleep apnea (OSA) is well known for its metabolic as well as neurobehavioral consequences. Chronic intermittent hypoxia (IH) is a major component of OSA. In recent years, substantial advances have been made in elucidating the cellular and molecular mechanisms underlying the effect of chronic IH on neurocognitive functions, many of which are based on studies in animal models. A number of hypotheses have been put forward to explain chronic IH-induced neurological dysfunctions. Among these, the roles of oxidative stress and apoptosis-related neural injury are widely accepted. Here, focusing on results derived from animal studies, we highlight a possible role of reduced expression of brain-derived neurotrophic factor (BDNF) in causing impairment in long-term synaptic plasticity and neurocognitive functions during chronic IH. The possible relationship between BDNF and previous findings on this subject will be elucidated.

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Pharmacology of Ampakine Modulators: From AMPA Receptors to Synapses and Behavior

Cited by 186 publications

References 0 publications

Synaptic evidence for the efficacy of spaced learning

Synaptic evidence for the efficacy of spaced learning

A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists

Chronic intermittent hypoxia-induced deficits in synaptic plasticity and neurocognitive functions: a role for brain-derived neurotrophic factor

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