The Calcium-Binding Protein S100A10 (p11) Is Required for Normal Motor Performance by Regulating Vesicle Dynamics at Excitatory Synapses.

AIM: Identifying interactors in sensorimotor processing and neurotransmission remains a current challenge for understanding neural information processing and brain function.

METHODS

To evaluate the role of p11 in sensorimotor processing and excitatory synaptic neurotransmission, neuron-specific lentivirus-directed p11 silencing, small interfering RNA (siRNAp11)-induced p11 deletion, unitary extracellular recordings of hypoglossal motor neurons (HMNs), western blot, co-immunoprecipitation, multiple immunolabeling, proximity ligation (PLA) assays, electron microscopy, and whole-cell patch-clamp recording of AMPA receptor-mediated excitatory postsynaptic currents in adult and/or neonatal rat HMNs were performed.

RESULTS

p11 knockdown depressed baseline and chemoreceptor-modulated inspiratory-related activity in HMNs. Co-immunoprecipitation and PLA assays indicated that p11 interacts with Munc13-1, a presynaptic active zone (AZ) protein for vesicle priming, presumably at excitatory inputs in the hypoglossal nucleus. Interference with p11 resulted in Munc13-1 downregulation, reduction in AZ length, and increased vesicle accumulation at excitatory boutons on HMNs, without affecting the number of docked vesicles at the AZ. p11 knockdown robustly reduced the synaptic strength of excitatory neurotransmission incoming to HMNs by affecting both the synchronous and asynchronous phases of neurotransmitter release. The decrease in synaptic strength was concurrent with a reduction in the size of the "functional" pool of readily releasable (RRP) vesicles and with the slowing down of the vesicle recruitment rate to replenish RRP.

CONCLUSION

p11 is proposed as a relevant mediator in the neurotransmitter release by regulating vesicle dynamics at central excitatory synapses. Here, p11 is highlighted as a multifaceted factor involved in neurotransmission and synaptic plasticity and, therefore, central for neural information processing.