How Gene Expression Controls Synaptic Plasticity in the Aging Human Brain
Summary: M1 muscarinic acetylcholine receptor (mAChR)-dependent LTP and LTD share a common AMPA trafficking pathway. Either upregulation of neurotransmitter receptor genes or suppression of downregulation can ameliorate synaptic dysfunction associated with age-related neurodegeneration. The findings could help create new therapies for Alzheimer’s disease that target synaptic plasticity.
Source: Okayama University
Scientific evidence shows that cognitive decline in Alzheimer’s disease (AD) is caused by the accumulation of beta amyloid proteins, which promote synaptic dysfunction.
One of the neuropathological features in the brains of AD patients is the degeneration of basal forebrain cholinergic neurons, leading to a decrease in the number of cholinergic projections to the hippocampus. As a symptomatic treatment of AD, cholinergic neurotransmission is improved by the use of certain drugs known as acetylcholinesterase inhibitors.
To better prevent and treat cognitive disorders such as AD and schizophrenia, it is necessary to understand how acetylcholine regulates synaptic transmissions.
Higher brain functions, such as learning and memory, are regulated in part 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 hippocampus-controlled learning activities, extracellular acetylcholine (Ach) levels increase 4-fold in the hippocampus, driven by mAChR signal transduction. Activation of mAChRs 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, scientists from Japan have recently created a model to track hippocampal synaptic plasticity.
Their study is published in Volume 26, Issue 3 of iScience.
Associate Professor Tomonari Sumi from Okayama University, Japan, who led the study, explains, “Here, we propose the hypothesis that M1 mAChR-dependent LTP and LTD share the common α-amino-3-hydroxy5-methyl-4-isoxazolepropionic acid receptor. acid.(AMPAR) trafficking pathway associated with NMDAR-dependent LTP and LTD.”
For hippocampal neurons, an AMPA receptor (AMPAR) trafficking model was proposed to simulate N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity. The findings of this study validate the hypothesis that mAChR-dependent LTP and LTD share a common AMPAR trafficking pathway.
The difference between the two pathways is that upon M1-mAChR activation, Ca2+ ions stored in the endoplasmic reticulum of neurons are released into the spine cytosol. A competition between Ca2+-dependent exocytosis and endocytosis regulates 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 the expression of new genes is not necessary, at least in the early stages of LTP and LTD. ” says Kouji Harada of the Center for IT-Based Education, Toyohashi University of Technology.
During hippocampus-controlled learning activities, extracellular acetylcholine (Ach) levels increase 4-fold in the hippocampus, driven by mAChR signal transduction. Activation of mAChRs by agonists (activating chemicals) is known to induce LTP and LTD in the hippocampus, but the underlying molecular mechanisms are not well understood. The image is in the public domain
These findings show how the reduction in the number of AMPARs due to different levels of gene expression affects the induction of LTP and LTD. These results will be useful to understand the dominant factors resulting in LTP and LTD changes in animal models of AD, which may ultimately be very useful for the development of AD therapy targeting synaptic plasticity for humans. .
Aging of the human brain causes a marked reduction in the expression of a number of neurotransmitter receptors, such as GluA1, which promotes the integration of AMPA receptors within synaptic membranes. The AMPAR trafficking model indicates that the changes in LTP and LTD observed in AD may be due to the age-related reduction in AMPAR expression levels.
“Taken together, these observations suggest that neurotransmitter receptor gene upregulation or suppression of downregulation may ameliorate synaptic dysfunction during AD.” says Dr. Sumi.
About this news about synaptic plasticity research
Author: Ryoko Mimura
Source: Okayama University
Contact: Ryoko Mimura – Okayama University
Image: Image is in the public domain
Original Research: Open Access.
“Muscarinic acetylcholine receptor-dependent and NMDA receptor-dependent LTP and LTD share common AMPAR trafficking pathway” by Tomonari Sumi et al. Science
Muscarinic acetylcholine receptor-dependent LTP and LTD and NMDA receptor-dependent LTP and LTD share a common AMPAR trafficking pathway
Highlights M1 mAChR- and NMDAR-dependent LTP and LTD share a common AMPAR trafficking pathway Competition between exocytosis and Ca2+-dependent endocytosis regulates LTP and LTDA simple reduction in the number of AMPARs attenuates LTP and potentiates LTD Synaptic dysfunction is assocd. with cognitive diseases.
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 mAChRs. An AMPA receptor (AMPAR) trafficking model for hippocampal neurons has been proposed to simulate early-stage N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity.
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 NMDARs, Ca2+ influx into the spine cytosol occurs due to Ca2+ stored within the ER and is induced via activation of inositol 1,4,5-trisphosphate (IP3) receptors during M1 mAChR activation.
Furthermore, the AMPAR trafficking model implies that the changes in LTP and LTD observed in Alzheimer’s disease can be attributed to age-dependent reductions in AMPAR expression levels.