Amyloid-beta inhibits E-S plasticity and LTP through inhibition of cannabinoid receptor 1-dependent synaptic disinhibition
Abstract/Contents
- Abstract
- Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting the elderly that is characterized by loss of short-term memory and cognitive decline. Studies in both human patients and animal models of AD point to over-accumulation of soluble oligomers of amyloid-beta peptide (Abeta) as a mediator of learning and memory impairments early in the disease (Rowan, Klyubin et al. 2005; Selkoe 2008). Support for Abeta's role in learning deficits comes from studies demonstrating impaired plasticity of synaptic inputs to neurons, as measured in the paradigm of long-term potentiation (LTP) of synaptic strength in hippocampal slices (Chen, Kagan et al. 2000; Freir, Holscher et al. 2001; Walsh, Klyubin et al. 2002; Wang, Pasternak et al. 2002; Townsend, Shankar et al. 2006), the prime candidate for the neuronal substrate of learning and memory behavior (Bliss and Collingridge 1993). Induced concurrently with synaptic LTP is an increase in the electrical coupling between the dendritic synaptic inputs and the soma, such that a greater proportion of the EPSP survives at the spike trigger zone, resulting in greater action potential output for a given EPSP. This potentiation of EPSP-spike coupling (E-S coupling) provides an additional boost to the efficacy of the EPSP on top of the potentiation (LTP) that occurs at the synapse (Bliss and Lomo 1973). While LTP of synaptic strength is an essential component of memory storage, in all models of learning, memory recall occurs only when spikes are evoked in the neurons participating in a representation. Thus E-S potentiation exerts control over the essential substrate of memory retrieval. Although LTP and E-S potentiation are mechanistically distinct processes, several features during the induction phase are shared. Studies have shown that Abeta impairs the induction, but not maintenance of LTP (Wang, Walsh et al. 2004; Townsend, Shankar et al. 2006), leaving the possibility that Abeta-mediated impairment to memory is not specific to LTP. Nevertheless, focus has centered on pathways central to LTP, while impairment to other forms of plasticity have not been explored. Here we show a mechanism by which Abeta peptides impairs post-tetanic suppression of inhibition, thereby inhibiting E-S potentiation. This impairment to E-S potentiation was occluded by GABAA-receptor, Cannabinoid 1 receptor (CB1R), and muscarinic acetylcholine receptor (mAChR), but not mGluR block. This suggests that the impairment is mediated by mAChR-initiated endocannbinoid signaling. Together, the results provide a mechanism to explain learning and memory impairments in early Alzheimer's disease.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2010 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Orr, Adrienne Lee |
|---|---|
| Associated with | Stanford University, Department of Molecular and Cellular Physiology. |
| Primary advisor | Madison, Daniel V, 1956- |
| Thesis advisor | Madison, Daniel V, 1956- |
| Thesis advisor | MacIver, M. Bruce (Murdo Bruce) |
| Thesis advisor | Smith, Stephen |
| Thesis advisor | Wyss-Coray, Anton |
| Advisor | MacIver, M. Bruce (Murdo Bruce) |
| Advisor | Smith, Stephen |
| Advisor | Wyss-Coray, Anton |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Adrienne Orr. |
|---|---|
| Note | Submitted to the Department of Molecular and Cellular Physiology. |
| Thesis | Ph.D. Stanford University 2010 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2010 by Adrienne Lee Orr
- License
- This work is licensed under a Creative Commons Attribution 3.0 Unported license (CC BY).
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