Neuroplastin 65 mediates cognitive functions via excitatory/inhibitory synapse imbalance and ERK signal pathway

•Neuroplastin 65 (NP65) in mice was knocked out by gene targeting.•NP65 KO mice exhibited enhanced hippocampus-dependent learning and memory.•NP65 KO mice showed anxiety-like behaviors.•NP65 deletion caused enhanced ratio of excitatory to inhibitory synapses.•NP65 deletion enhanced activation of ERK1/2 signaling.

Neuroplastin 65 (NP65) is a brain-specific glycoprotein component of synaptic membrane, which is predominantly located in the forebrain such as the cortex, amygdala and striatum and hippocampus. Previous studies have shown that NP65 is implicated in synaptic plasticity, so it was hypothesized to play roles in cognitive functions. To test this hypothesis, we generated NP65 knock-out (KO) mice and found that the null mice exhibited enhanced hippocampus-dependent learning and memory as manifested by Morris water maze test and step-through passive avoidance test, but showed anxiety-like behaviors as manifested by open field test and light/dark exploration test. In addition, molecular and cellular studies revealed several alterations including: (1) the enhanced ratio of excitatory to inhibitory synapses; (2) increased expression of NMDA receptors NR2A; (3) enhanced activation of ERK signaling; (4) lowered number of the mushroom- and bifurcate-shaped dendritic spines in NP65 KO mice. Together, our findings suggest that NP65 may mediate cognitive functions.