THE EFFECTS OF REDUCED ENDOGENOUS OXYTOCIN RELEASE ON COGNITIVE FUNCTION IN CAPS2 CKO MICE

Abstract Background & Objectives Recently, we found that the mice treated with oxytocin (OXT) improved the amyloid-β induced memory dysfunction. In addition, plasma OXT levels have been reported to be lower in Alzheimer’ s disease (AD) patients than in healthy individuals, proposing that decreasing the secretion of OXT could be a risk factor for the development of AD. However, it is unknown whether decreased OXT levels affect cognitive functions. We previously developed mice with OXT neuron-specific deficiency of the Ca2+-dependent activator protein for secretion (CAPS) (Caps2 conditional KO (cKO) mice) and found that plasma OXT level was decreased in these mice. In this study, we examined the effects of reduced OXT release on cognitive function in Caps2 cKO mice. Results We firstly investigated the OXT receptors mRNA in hippocampus. OXT receptors mRNA was significantly increased in Caps2 cKO mice compared to Caps2flox/flox mice. In Caps2 cKO mice, object memory in the novel object recognition (NOR) test and fear memory in the passive avoidance (PA) test were impaired, respectively, but short-term spatial memory in the Y-maze test was not. The cognitive dysfunction observed in Caps2 cKO mice observed in the NOR and PA tests was reversed by intracerebroventricular administration of OXT. In addition, hippocampal long-term potentiation (LTP) was reduced in Caps2 cKO mice compared to Caps2flox/flox mice without affecting the paired-pulse ratio or input-output curve. Further, the expression of phosphorylated ERK (pERK) in the ventral hippocampus was reduced in the Caps2 cKO mice compared to Caps2flox/flox mice. Discussion & Conclusion These results indicate that deletion of CAPS2 in OXT neurons impairs synaptic plasticity via the ERK signaling pathway in the hippocampus, which may result in impairment of cognitive functions such as object recognition and fear memory. This study is expected to provide insight into the relationship between the activity of the oxytocin nervous system in the brain and cognitive function.