m1 muscarinic receptors
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2021 ◽  
Author(s):  
Louis Dwomoh ◽  
Mario Rossi ◽  
Miriam Scarpa ◽  
Elham Khajehali ◽  
Colin Molloy ◽  
...  

The most prevalent types of dementias, including Alzheimer's disease, are those that are propagated via the spread of 'prion-like' misfolded proteins. Despite considerable effort, no treatments are available to slow or stop the progression of these dementias. Here, we investigate the possibility that activation of the M1-muscarinic receptor (M1-receptor), which is highly expressed in the brain and that shows pro-cognitive properties, might present a novel disease modifying target. We demonstrate that the progression of murine prion disease, which we show here displays many of the pathological, behavioural and biochemical hallmarks of human neurodegenerative disease, is slowed and normal behaviour maintained by the activation of the M1-receptor with a highly tolerated positive allosteric modulator (VU846). This correlates with a reduction in both neuroinflammation and indicators of mitochondrial dysregulation, as well as a normalisation in the expression of markers associated with neurodegeneration and Alzheimer′s disease. Furthermore, VU846 preserves expression of synaptic proteins and post-synaptic signalling components that are altered in disease. We conclude that allosteric regulation of M1-receptors has the potential to reduce the severity of neurodegenerative diseases caused by the ″prion-like″ propagation of misfolded protein in a manner that extends life span and maintains normal behaviour.


2020 ◽  
Vol 22 (1) ◽  
pp. 67
Author(s):  
Cassidy E. Wideman ◽  
James Nguyen ◽  
Sean D. Jeffries ◽  
Boyer D. Winters

Reminder cues can destabilize consolidated memories, rendering them modifiable before they return to a stable state through the process of reconsolidation. Older and stronger memories resist this process and require the presentation of reminders along with salient novel information in order to destabilize. Previously, we demonstrated in rats that novelty-induced object memory destabilization requires acetylcholine (ACh) activity at M1 muscarinic receptors. Other research predominantly has focused on glutamate, which modulates fear memory destabilization and reconsolidation through GluN2B- and GluN2A-containing NMDARs, respectively. In the current study, we demonstrate the same dissociable roles of GluN2B- and N2A-containing NMDARs in perirhinal cortex (PRh) for object memory destabilization and reconsolidation when boundary conditions are absent. However, neither GluN2 receptor subtype was required for novelty-induced destabilization of remote, resistant memories. Furthermore, GluN2B and GluN2A subunit proteins were upregulated selectively in PRh 24 h after learning, but returned to baseline by 48 h, suggesting that NMDARs, unlike muscarinic receptors, have only a temporary role in object memory destabilization. Indeed, activation of M1 receptors in PRh at the time of reactivation effectively destabilized remote memories despite inhibition of GluN2B-containing NMDARs. These findings suggest that cholinergic activity at M1 receptors overrides boundary conditions to destabilize resistant memories when other established mechanisms are insufficient.


2020 ◽  
Vol 152 (12) ◽  
Author(s):  
Tamas Balla

New findings by Myeong et al. provide further details on how cells maintain their plasma membrane PI(4,5)P2 levels when stimulated via M1 muscarinic receptors


2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Kristen H. Jardine ◽  
Cassidy E. Wideman ◽  
Chelsea MacGregor ◽  
Cassandra Sgarbossa ◽  
Dean Orr ◽  
...  

2019 ◽  
Vol 858 ◽  
pp. 172474
Author(s):  
Mohamed Kreir ◽  
An De Bondt ◽  
Ilse Van den Wyngaert ◽  
Greet Teuns ◽  
Hua Rong Lu ◽  
...  

2019 ◽  
Vol 146 ◽  
pp. 242-251 ◽  
Author(s):  
Cai-Hong Xiong ◽  
Ming-Gang Liu ◽  
Lan-Xue Zhao ◽  
Mu-Wen Chen ◽  
Ling Tang ◽  
...  

2019 ◽  
Vol 33 (5) ◽  
pp. 6622-6631 ◽  
Author(s):  
Lan‐Xue Zhao ◽  
Yan‐Hui Ge ◽  
Jia‐Bing Li ◽  
Cai‐Hong Xiong ◽  
Ping‐Yee Law ◽  
...  

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