Neurotransmitter release progressively desynchronizes in induced human neurons during synapse maturation and aging
Burak Uzay,
Aiden Houcek,
Z. Zack Ma,
Christine Konradi,
Lisa M. Monteggia,
Ege T. Kavalali
Affiliations
Burak Uzay
Brain 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
Aiden Houcek
Brain 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
Z. Zack Ma
Brain 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
Christine Konradi
Brain 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
Lisa M. Monteggia
Brain 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
Ege T. Kavalali
Brain 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; Corresponding author
Summary: Rapid release of neurotransmitters in synchrony with action potentials is considered a key hardwired property of synapses. Here, in glutamatergic synapses formed between induced human neurons, we show that action potential-dependent neurotransmitter release becomes progressively desynchronized as synapses mature and age. In this solely excitatory network, the emergence of NMDAR-mediated transmission elicits endoplasmic reticulum (ER) stress leading to downregulation of key presynaptic molecules, synaptotagmin-1 and cysteine string protein α, that synchronize neurotransmitter release. The emergence of asynchronous release with neuronal maturity and subsequent aging is maintained by the high-affinity Ca2+ sensor synaptotagmin-7 and suppressed by the introduction of GABAergic transmission into the network, inhibition of NMDARs, and ER stress. These results suggest that long-term disruption of excitation-inhibition balance affects the synchrony of excitatory neurotransmission in human synapses.
