Neurotransmitter release progressively desynchronizes in induced human neurons during synapse maturation and aging

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 endo-plasmic reticulum (ER) stress leading to downregulation of key presynaptic molecules, synaptotagmin-1 and cysteine string protein a, 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.

Automated summary

The rapid release of neurotransmitters in synapses is considered an important property, but as synapses mature and age, the release becomes progressively desynchronized. This is caused by NMDAR-mediated transmission leading to ER stress and downregulation of key presynaptic molecules. The emergence of asynchronous release is maintained by synaptotagmin-7 and can be suppressed by GABAergic transmission, inhibition of NMDARs, and ER stress. Long-term disruption of the excitation-inhibition balance affects the synchrony of excitatory neurotransmission in human synapses.