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Neurotransmitter release progressively desynchronizes in induced human neurons during synapse maturation and aging
Burak Uzay1, Aiden Houcek1, Z Zack Ma1
1Brain Institute, Vanderbilt University, Nashville, TN 37240-7933, USA; Department of Pharmacology, Vanderbilt University, 7130A MRB III 465 21st Avenue South, Nashville, TN 37240-7933, USA.
Cell Reports
|January 26, 2023
Summary
Synaptic transmission becomes desynchronized with aging in human neurons. This occurs due to endoplasmic reticulum stress impacting key molecules that regulate neurotransmitter release.
Area of Science:
- Neuroscience
- Synaptic Plasticity
- Cellular Aging
Background:
- Synchronous neurotransmitter release with action potentials is a fundamental synaptic property.
- Understanding synaptic function during maturation and aging is crucial for neurological health.
Purpose of the Study:
- To investigate changes in action potential-dependent neurotransmitter release synchrony in mature and aging human glutamatergic synapses.
- To identify molecular mechanisms underlying the emergence of asynchronous release.
Main Methods:
- Utilized induced human neurons to form glutamatergic synapses.
- Examined neurotransmitter release patterns during synaptic maturation and aging.
- Investigated the roles of NMDARs, ER stress, synaptotagmin isoforms, and GABAergic transmission.
Main Results:
- Action potential-dependent neurotransmitter release became progressively desynchronized in maturing and aging human synapses.
- NMDAR activation induced endoplasmic reticulum (ER) stress, downregulating synaptotagmin-1 and cysteine string protein α.
- Synaptotagmin-7 maintained asynchronous release, which was suppressed by GABAergic transmission, NMDAR inhibition, and ER stress.
Conclusions:
- Synaptic maturation and aging lead to desynchronization of excitatory neurotransmission in human synapses.
- ER stress and altered presynaptic molecule expression are key drivers of asynchronous release.
- Disruption of excitation-inhibition balance impacts excitatory neurotransmission synchrony.
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