Cerebral dopamine neurotrophic factor (CDNF) is the promising tool for treatment of Parkinson’s disease. However, its role in the regulation of non-motor behavior, including various psychopathologies, remains unclear. In this regard, the aim of present work was to study the effect of CDNF overexpression in the hippocampus on the behavior of ASC mice (Antidepressant Sensitive Cataleptics) with a genetic predisposition to depression-like behavior. CDNF overexpression in mouse hippocampal neurons was induced using an adeno-associated viral vector. Four weeks after stereotaxic injection of the AAV-CDNF construct into the dorsal hippocampus, home cage behavior, exploratory, anxiety and depressive-like behaviors, as well as spatial and associative learning were assessed. We found significant improvements in the dynamics of spatial learning in the Morris water maze in CDNF-overexpressing animals. At the same time, no effect of CDNF was found on other studied behaviors. The behavior of the experimental animals in the home cage conditions did not differ from that in the control group, except for a decrease in the total amount of food eaten and a slight increase in the number of sleep episodes in the light phase of the day. In the present study we also attempted to determine the molecular basis for the above mentioned changes by genes expression assessment. We did not find significant changes in the mRNA level of key kinases, genes involved in neuroplasticity and neuronal survival as well as genes encoding receptors for the main neurotransmitter systems. However, animals overexpressing CDNF show increased lever of spliced Xbp indicating activation of the Ire1α/Xbp1 pathway traditionally associated with ER stress. Immunohistochemical analysis showed that CDNF was co-localized with the ER marker calreticulin. Thus, the effects of endogenous CDNF on behavior that we have found may be mediated by a specific molecular cascade, which emphasizes its difference from classical neurotrophic factors.