Neuropeptide S promotes maintenance of newly formed dendritic spines and performance improvement after motor learning in mice.

Neuropeptide S (NPS), an endogenous neuropeptide consisting of 20 amino acids, selectively binds and activates G protein-coupled receptor named neuropeptide S receptor (NPSR) to regulate a variety of physiological functions. NPS/NPSR system has been shown to play a pivotal role in regulating learning and memory in rodents. However, it remains unclear that how NPS/NPSR system affects neuronal functions and synaptic plasticity after learning. We found that intracerebroventricular (i.c.v.) injection of NPS promoted performance improvement and reduced sleep duration after motor learning, which could be blocked by pre-treatment with intraperitoneal (i.p.) injection of NPSR antagonist SHA 68. Using intravital two-photon imaging, we examined the effect of NPS on the postsynaptic dendritic spines of layer V pyramidal neurons in the mouse primary motor cortex after motor learning. We found that i.c.v. injection of NPS strengthened learning-induce new spines and facilitated their survival over time. Furthermore, i.c.v. injection of NPS increased calcium activity of apical dendrites and dendritic spines of layer V pyramidal neurons in the mouse primary motor cortex during the running period. These findings suggest that activation of NPSR by NPS increases synaptic calcium activity and learning-related synapse maintenance, thereby contributing to performance improvement after motor learning.