Vasopressin somatodendritic release inhibits firing activity in an autocrine manner by enhancing the slow afterhyperpolarization

Vasopressin (VP) magnocellular neurons display phasic firing patterns that optimize peptide release. This activity is underlain by intrinsic mechanisms such as the slow afterhyperpolarization (sAHP). This Ca 2+ -dependent K + conductance activates during firing to hyperpolarize the neuron, inducing spike frequency adaptation (SFA) and terminating bursting. Interestingly, VP inhibits these neurons by binding to cognate V1aR receptors, but it is unknown whether sAHP modulation contributes to this inhibitory effect. We hypothesized that VP somatodendritic release (SDR) inhibits VP neurons in an autocrine manner by enhancing sAHP magnitude. We tested this hypothesis using a combination of whole cell patch clamp, Ca 2+ imaging, and photolytic uncaging. VP bath application enhanced the overall sAHP magnitude evoked by spikes, which reflected as an increase in SFA during the evoked train. By contrast, V1aR antagonism (SR49059) by itself failed to affect sAHPs or SFA. These results suggest that during evoked spike trains, there is insufficient VP SDR to modulate the sAHP. We previously showed that spiking evoked by NMDA receptor (NMDAR) activation (but not via direct depolarization) efficiently evoked SDR of VP (Pitra et al. 2019). To test whether spike-induced endogenous SDR of VP was sufficient to modulate sAHPs in an autocrine manner, we evoked spikes via NMDAR activation. To this end, we used focal glutamate uncaging in the presence of synaptic blockers (DNQX and picrotoxin) to isolate NMDARs. We found that the NMDAR-evoked spike count significantly increased in the presence of SR49059. This suggests that NMDAR-evoked VP SDR may contribute to terminating bursts. We recently showed that sAHP activation in VP neurons requires the release of endoplasmic reticulum (ER) Ca 2+ (Kirchner et al., 2024). Thus, we repeated focal NMDAR activation following the depletion of ER Ca 2+ stores (1 h thapsigargin (TG) preincubation). NMDAR activation evoked significantly longer spike trains in TG, suggesting that the sAHP underlies the SFA observed after NMDAR activation. Finally, we directly tested the ability of autocrine VP SDR to enhance the sAHP. We repeatedly triggered sAHPs via current depolarization before and after a single uncaging event of NMDAR-evoked VP SDR from the same neuron. sAHPs were markedly enhanced (for ~2 minutes) following VP SDR evocation. Together, these results describe an intrinsic mechanism by which VP SDR produces its autoinhibitory action, wherein V1aR activation enhances the sAHP, slowing down firing in the activated neuron. How this phenomenon operates in response to physiological challenges and whether its impairment contributes to enhanced VP activity and release in disease conditions such as heart failure, where the overall AHP is greatly inhibited, remains to be elucidated. NIH K99 HL168434 (M.K.K.); NIH R01 HL162575-01 (J.E.S.) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.