Oxytocin enhances excitability and potentiates synaptic transmission in dentate gyrus granule cells

Abstract

The dentate gyrus is the principal gateway for information into the hippocampus. The dentate gyrus transforms input from the entorhinal cortex into sparse, selective representations that support memory formation. Oxytocin is a key neuromodulator of social behavior and supports social memory through its actions in hippocampal area CA2. However, whether oxytocin also modulates the dentate gyrus (DG), a source of major excitatory input to CA2, remains unclear. We performed whole-cell recordings to test if oxytocin modulated the excitability of mouse dentate gyrus granule cells. We found that bath application of the oxytocin receptor agonist Thy4, Gly7-oxytocin (TGOT) increased DG granule cell excitability by depolarizing the resting membrane potential, increasing input resistance, and hyperpolarizing action potential threshold. In addition to increasing postsynaptic excitability, we found that TGOT decreased the paired-pulse ratio of perforant path to granule cell synapses and also increased the frequency, without an effect on amplitude, of miniature EPSCs suggesting that TGOT increased the probability of glutamate release. Notably, long-term potentiation induced by theta-burst pairing occluded the effect of TGOT on synaptic strength suggesting that oxytocin and long-term potentiation may converge on common downstream mechanisms. Our results revealed a previously uncharacterized role for oxytocin in regulating the relay of information between the entorhinal cortex and dentate gyrus. This suggests a potential mechanism through which oxytocin shapes hippocampal processing of socially relevant stimuli. Significance StatementOxytocin is essential for social memory and acts prominently within hippocampal area CA2, yet its influence on the dentate gyrus, a major excitatory input of CA2, has remained unclear. We demonstrate that oxytocin modulates dentate gyrus granule cell signaling by enhancing intrinsic excitability and strengthening perforant path synaptic transmission via increased presynaptic release probability. We further show that long-term potentiation occludes these synaptic effects suggesting convergence between oxytocin signaling and activity-dependent plasticity. These findings identify a previously unrecognized role for oxytocin in shaping dentate gyrus processing, broadening our understanding of how neuromodulatory signals influence hippocampal circuits involved in social information processing. Key pointsO_LIOxytocin increases dentate gyrus granule cell excitability by depolarizing resting membrane potential, increasing input resistance and hyperpolarizing action potential threshold. C_LIO_LIOxytocin enhances perforant path synaptic transmission by increasing presynaptic glutamate release probability. C_LIO_LILong-term potentiation occludes the synaptic effects of oxytocin, suggesting overlap in downstream mechanisms. C_LI