TWO-PORES CHANNELS ARE KEY MEDIATORS OF OXYTOCIN SIGNALING AND MATERNAL BEHAVIOR

The hypothalamic oxytocinergic circuit is essential for maternal behavior. Astroglial modulations of oxytocinergic neurons is well known to play a prominent role in this process. In particular, several studies have proposed that oxytocin itself enables astroglial modulation of neuronal activity. However, the underlying mechanisms involved remain unresolved. Here, we investigated the role of the lysosomal calcium channels TPCs in oxytocinergic signaling regulating maternal behavior. Using the pup retrieval test, we observed that TPC knockout mice exhibit significant maternal deficits, characterized by increased latency and reduced efficiency in pup retrieval. These behavioral impairments correlate with a marked reduction in plasma oxytocin levels. Given the critical role of astrocytes in the modulation of oxytocinergic neurons during maternity, we next examined whether TPCs are involved in oxytocin-evoked astrocytic calcium responses. To address this, we performed calcium imaging in hypothalamic slices from mice expressing GCaMP6 selectively in astrocytes. Recording were obtained from astrocytes of the paraventricular nucleus (PVN) and combined with pharmacological inhibition of TPCs. As expected, oxytocin robustly induced calcium elevations in astrocytes under control conditions. Strikingly, these oxytocin-evoked calcium signals were completely abolished in the presence of TPC antagonists, demonstrating a mandatory role for TPCs in astroglial oxytocinegic signaling. Together, our results show that TPCs regulate systemic oxytocin release and maternal behavior and are key mediators of oxytocin-dependent neuroglial interactions. These findings identify lysosomal calcium signaling as a novel component of oxytocin signaling, with potential implications for understanding and treating social and maternal behavioral disorders.