- Dorsal hippocampus is essential for cognitive flexibility, contributing beyond prefrontal-striatal networks.
- RNF10 links synaptic NMDAR activation to dorsal CA1 transcriptional programmes required for cognitive flexibility.
- In vivo RNF10 deletion or silencing impairs long-term synaptic plasticity and hinders adapting behaviour to changed contexts.
iScience. 2026 Sep 25;29(10):117651. doi: 10.1016/j.isci.2026.117651. eCollection 2026 Oct 16.
ABSTRACT
The ability to flexibly adapt behavior to changing environmental contingencies is a core component of brain function and relies on experience-dependent remodeling of neural circuits. While cognitive flexibility has been primarily attributed to prefrontal-striatal networks, the contribution of hippocampus and its underlying molecular substrates remains less understood. Here, we show that the dorsal hippocampus has a key role in cognitive flexibility. Ring finger protein 10 (RNF10)-mediated signaling, linking activation of synaptic N-methyl-D-aspartate receptors (NMDARs) to specific transcriptional programs in the dorsal CA1, is necessary for cognitive flexibility. In fact, in vivo downregulation, through gene deletion and silencing of RNF10, resulting in impaired long-term synaptic plasticity, suppressed cognitive flexibility. This was reflected in the impaired ability to disengage from previously acquired contextual, visual, and spatial information and to adapt behavior to changed context. Overall, we identified RNF10 as a key in vivo player necessary for the balance between cognitive stability and flexibility.
PMID:42835301 | PMC:PMC13635533 | DOI:10.1016/j.isci.2026.117651
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