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RNF10 as an NMDA receptor-dependent signaling protein necessary for cognitive flexibility

ABSTRACT: Activation of synaptic N-methyl-D-aspartate receptors (NMDARs) drives the nuclear translocation of synaptonuclear messengers involved in the transcriptional program engaged in synaptic plasticity. However, the role of synaptonuclear messengers in regulating cognitive behavior has not been fully clarified. Here, we demonstrated that RNF10-mediated synapse-to-nucleus signaling, linking activation of synaptic NMDARs to nuclear gene expression in the dorsal CA1, is necessary for cognitive flexibility. In vivo RNF10 downregulation, through gene deletion and silencing, induced alterations in dendritic branching, spine morphology, and long-term potentiation, specifically in CA1. At the behavioral level, we observed poor cognitive flexibility, which is reflected in the impaired ability to disengage from previously acquired contextual, visual, and spatial information. Overall, our results identified RNF10 as a key in vivo player necessary for the correct expression of cognitive flexibility.

ORGANISM(S): Mus musculus

PROVIDER: GSE245221 | GEO | 2026/08/27

REPOSITORIES: GEO

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Project description:Background: Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a Cdkl5-/y rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function underlie the enhanced LTP we observe in the hippocampus of Cdkl5-/y rats. Methods: To allow cross-species comparisons of phenotypes associated with the loss of CDKL5, we generated a loss of function mutation in exon 5 of the rat Cdkl5 gene and assessed the impact of the loss of CDLK5 using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology. Results: Our results indicate that CA1 hippocampal LTP is enhanced in slices prepared from juvenile, but not adult, Cdkl5-/y rats. Enhanced LTP does not result from changes in NMDA receptor function or subunit expression as these remain unaltered throughout development. Furthermore, Ca2+ permeable AMPA receptor mediated currents are unchanged in Cdkl5-/y rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability at Schaffer collateral to CA1 PC synapses. Conclusions: Our data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits contribute to the altered plasticity. Limitations: This study has focussed on the electrophysiological and anatomical properties of hippocampal CA1 PCs across early postnatal development. Studies involving other brains regions, older animals and behavioural phenotypes associated with the loss of CDKL5 are needed to understand the pathophysiology of CDD.

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RNF10 as an NMDA receptor-dependent signaling protein necessary for cognitive flexibility

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