Balsamo, B. | bioRxiv Science

bioRxiv2025

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

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

neuroscience↗

bioRxiv2025

Pathological α-Synuclein Perturbs Nuclear Integrity

Pathological aggregates of -synuclein are a hallmark of a group of neurodegenerative disorders collectively termed synucleinopathies. The physiological function of -synuclein, and the detrimental effects of the pathological variants of -synuclein have been widely debated, but recent evidence has suggested an emerging consensus on a critical role for -synuclein in regulating synaptic function. However, a controversial role for -synuclein in nuclear function in both normal and pathogenic states has been proposed, and the degree to which -synuclein localizes within the nucleus and subsequent impact on the nucleus are poorly understood. To begin to address this controversy, we employed synucleinopathy murine and cell culture models, as well as postmortem human Lewy Body Dementia tissue to elucidate the extent to which pathological -synuclein localizes within the nuclear compartments, and the downstream consequences of this localization. We observed pathological aggregation of -synuclein within the nucleus in both murine models and human postmortem Lewy Body Dementia cortex via quantitative super resolution microscopy. In both mouse and human brain tissue the presence of -synuclein in the nucleus correlated with abnormal morphology of nuclei. This pathological accumulation of -synuclein in the nucleus was not observed in control mice, human tissue without pathology, or control cells. We subsequently examined the mechanistic consequences of pathological accumulation of -synuclein in the nucleus. Synucleinopathy models displayed increased levels of the DNA damage marker 53BP1. Furthermore, cells with pathological -synuclein exhibited elevated markers of nuclear envelope damage and abnormal expression of nuclear envelope repair markers. Our cell culture data also suggests altered RNA localization in response to pathological -synuclein accumulation within the nucleus. Lastly, we show that nuclear Lewy-like pathology leads to increased sensitivity to nuclear targeted toxins. Taken together, these results rigorously illustrate nuclear localization of pathological -synuclein with super resolution methodology and provide novel insight into the ensuing impact on nuclear integrity and function.

neuroscience↗