Summary: Muscarinic acetylcholine M1 receptor (mAChR)-dependent LTP and LTD share a common AMPA trafficking pathway. Either upregulation of neurotransmitter receptor genes or suppression of downregulation could ameliorate synaptic dysfunction associated with age-related neurodegeneration. The findings could aid in the creation of new therapies for Alzheimer’s disease that target synaptic plasticity.
Source: Okayama University
Scientific evidence shows how cognitive decline in Alzheimer’s disease (AD) is caused by the accumulation of beta-amyloid proteins, which promote synaptic dysfunction.
One of the neuropathological hallmarks of the brain of patients with AD is the degeneration of the basal cholinergic neurons of the forebrain, leading to a decrease in the number of cholinergic projections to the hippocampus. As a symptomatic treatment for AD, cholinergic neurotransmission is enhanced by the use of certain drugs, known as acetylcholinesterase inhibitors.
To better prevent and treat cognitive disorders like AD and schizophrenia, it is necessary to understand how acetylcholine regulates synaptic transmissions.
Higher brain functions, such as learning and memory, are partly regulated by signaling through the M1 muscarinic acetylcholine receptor (mAChR). mAChR also induces long-term potentiation (LTP) and long-term depression (LTD) of excitatory synaptic transmission in the hippocampus.
During hippocampal-controlled learning activities, extracellular acetylcholine (Ach) levels increase 4-fold in the hippocampus, driven by mAChR signal transmission. Activation of the mAChR by agonists (activating chemicals) is known to induce LTP and LTD in the hippocampus, but the underlying molecular mechanisms are not well understood.
To study these molecular mechanisms, Japanese scientists recently designed a model to track synaptic plasticity in the hippocampus.
Their study was published in volume 26 number 3 of iScience.
Associate Professor Tomonari Sumi of Okayama University, Japan, who led the study, explains: “Here, we propose the hypothesis that M1-dependent LTP and LTD mAChR share the common receptor for a-amino-3-hydroxy5-methyl-4-isoxazolepropionic acid. (AMPAR) traffic channel associated with NMDAR-dependent LTPs and LTDs.
For hippocampal neurons, an AMPA receptor (AMPAR) trafficking model has been proposed to simulate N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity. The results of this study prove the validity of the hypothesis that mAChR-dependent LTP and LTD share a common AMPAR trafficking pathway.
The difference between the two pathways is that in the activation of M1-mAChR, Ca2+ ions stored in the endoplasmic reticulum of neurons are released into the cytosol of the spine. A competition between Ca2+ dependent exocytosis and endocytosis regulate LTP and LPD.
“Therefore, it can be concluded that the M1 mAChR-dependent induction of LTP and LTD shares the common AMPAR trafficking pathway with NMDAR-dependent synaptic plasticity, and new gene expression is not required, at least in the early stages of LTP and LTD. ” says Kouji Harada of the Center for IT-Based Education, Toyohashi University of Technology.
These results show how the reduction in the number of AMPARs due to variable gene expression levels affects the induction of LTP and LTD. These results will be useful for understanding the dominant factors driving alterations of LTP and LTD in animal models of AD, which may ultimately be very useful for the development of AD therapy targeting synaptic plasticity in humans. ‘male.
The aging of the human brain leads to a marked decrease in the expression of several neurotransmitter receptors, such as GluA1, which induces the integration of AMPA receptors inside synaptic membranes. The AMPAR trafficking model shows that the alterations in LTP and LTD observed in AD could be due to an age-related reduction in AMPAR expression levels.
“Taken together, these observations suggest that upregulation of neurotransmitter receptor genes or suppression of downregulation may ameliorate synaptic dysfunction in AD.” said Dr. Sumi.
About this synaptic plasticity research news
Author: Ryoko Mimura
Source: Okayama University
Contact: Ryoko Mimura – Okayama University
Picture: Image is in public domain
See also
Original research: Free access.
“Muscarinic acetylcholine receptor-dependent and NMDA receptor-dependent LTP and LTD share the common AMPAR trafficking pathway” by Tomonari Sumi et al. iScience
Abstract
Muscarinic acetylcholine receptor-dependent and NMDA receptor-dependent LTP and LTD share the common AMPAR trafficking pathway
Strong points
- M1 LTPs and LTDs dependent on mAChR and NMDAR share the common AMPAR traffic pathway
- Competition between ca2+-dependent exocytosis and endocytosis regulate LTP and LTD
- A simple reduction in the number of AMPARs weakens LTP and strengthens LTD
- Synaptic dysfunction is correlated with cognitive decline in Alzheimer’s disease
Summary
The forebrain cholinergic system promotes higher brain function in part by signaling through the M1 muscarinic acetylcholine receptor (mAChR). Long-term potentiation (LTP) and long-term depression (LTD) of excitatory synaptic transmission in the hippocampus are also induced by mAChR. An AMPA receptor (AMPAR) trafficking model for hippocampal neurons has been proposed to simulate N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity in the early phase.
In this study, we demonstrated the validity of the hypothesis that mAChR-dependent LTP/LTD shares a common AMPAR trafficking pathway associated with NMDAR-dependent LTP/LTD.
However, unlike NMDAR, Ca2+ influx into the cytosol of the spine occurs due to Ca2+ stored inside the ER and is induced via activation of inositol 1,4,5-trisphosphate (IP3) receptors upon M1 mAChR activation.
Moreover, the AMPAR trafficking model implies that the alterations in LTP and LTD observed in Alzheimer’s disease could be attributed to age-dependent reductions in AMPAR expression levels.