Carrano, N. | bioRxiv Science

bioRxiv2026

Hippocampal Ring Finger Protein 10-dependent signaling supports cognitive flexibility

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 their underlying molecular substrates remains less understood. Here, we show that the dorsal hippocampus has a key role in cognitive flexibility. In particular, Ring Finger Protein 10 (RNF10)-mediated signaling, linking activation of synaptic 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, our results identified RNF10 as a key in vivo player necessary for the balance between cognitive stability and flexibility.

animal behavior and cognition↗

bioRxiv2024

Lactate potentiates NMDA receptor currents via an intracellular redox mechanism targeting cysteines in the C-terminal domain of GluN2B subunits: implications for synaptic plasticity

SummaryThrough the Astrocyte Neuron Lactate Shuttle, astrocyte-derived lactate fuels the high-energy demands of neurons and acts as a signaling molecule, promoting synaptic plasticity and memory consolidation. Lactate regulates neuronal excitability and modulates the expression of genes related to synaptic plasticity and neuroprotection, but the molecular mode for these signaling actions is uncertain. Using patch-clamp recordings in cultured cortical neurons, we found that lactate enhances both the amplitude and the inactivation time constant of NMDA receptor currents (INMDAR) evoked by brief applications of glutamate and glycine. Not reproduced by HCAR1 agonists, this modulation depends on monocarboxylate transporters and lactate dehydrogenase, indicating the requirement for lactate entry and metabolic conversion into pyruvate and NADH formation within neurons. Disruption of intracellular calcium dynamics or inhibition of Ca2+/calmodulin-dependent protein kinase II (CaMKII), a NMDAR-associated kinase linking Ca2+ signal to long-term potentiation (LTP), significantly diminishes the effects of lactate on INMDAR. We identified two redox-sensitive cysteine- containing sequences in the intrinsically disordered intracellular C-terminal domain of the GluN2B subunit that play a role in the potentiation of NMDAR by lactate. In a compelling set of experiments using HEK cells, we observed that the presence of functional CaMKII and GluN2B-containing NMDARs is necessary for the lactate-enhancing effects. Mutations in GluN2B that prevent CaMKII binding or redox regulation via cysteines abrogate the modulatory action of lactate. Immunoprecipitation experiments in neurons attest that lactate increases the association between CaMKII and GluN2B. This interaction is crucial for the potentiation of INMDAR amplitude by lactate. Proximity ligation assays between GluN2B and the postsynaptic density marker PSD-95 revealed that lactate induced an accumulation of GluN2B in dendritic spines, an effect that was prevented by a CaMKII peptide inhibitor. These results highlight a mechanistic pathway whereby lactate boosts NMDAR function through intracellular metabolic conversion and redox-sensitive interactions requiring CaMKII, establishing a link between astrocyte metabolism and synaptic modulation in neurons.

neuroscience↗