Cerebral dopamine neurotrophic factor (CDNF) affects hippocampal neuroplasticity and fear memory in rats

Abstract

The role of CDNF in modulating learning and memory remains largely unexplored. Here, hippocampal CDNF overexpression significantly accelerated extinction of contextual and cued fear memory in rats. Molecularly, overexpressed CDNF was retained in the ER and upregulated mRNA levels of Perk , Atf6 , and spliced Xbp1 , indicating activation of UPR-related signaling. Furthermore, CDNF overexpression increased CREB transcription and phosphorylation. Additionally, Cdnf mRNA levels correlated positively with transcript levels of Bdnf exons I, II, and IV. In primary hippocampal neurons, CDNF enhanced spontaneous bioelectrical activity, network burst complexity, and functional connectivity, as evidenced by multielectrode array and calcium imaging. These findings suggest that CDNF facilitates fear memory extinction, potentially through UPR-related signaling and enhanced neuronal excitability and network synchronization, positioning it as a potential regulator of hippocampal-dependent plasticity.