Differential effects of osmotic stress on synaptic vs. paracrine signaling mechanisms in oxytocinergic magnocellular neurons.
Authors: Frazier Charles Jason , Sheng Wanhui , Harden Scott W. 
Published: June 2021

Acute hypernatremia promotes natriuresis in part by increasing activity of oxytocinergic magnocellular neurons in the hypothalamus that promote synaptic release of oxytocin (OT) from axon terminals in the neurohypophysis. Acute hypernatremia also blunts stress‐induced activation of the hypothalamic‐pituitary‐adrenal axis via a mechanism that we believe is likely to depend on central paracrine (rather than synaptic) release of OT from magnocellular dendrites. Interestingly, prior work from other groups indicates that acute hypernatremia produces an increase in the concentration of circulating OT significantly more rapidly than it creates an increase in the concentration of central OT. The current project was designed to develop a better understanding of the underlying cellular mechanisms through which osmotic stressors may plausibly promote both synaptic and paracrine release of OT from the same population of osmosensitive hypothalamic neurons, but with distinctly different temporal dynamics. Towards that end, we used the Cre‐LoxP system to generate OT‐reporter mice that express tdTomato in neurons that synthesize OT. Initial studies indicated a strong colocalization of tdTomato with OT/neurophysin1 throughout the hypothalamus. Whole‐cell patch clamp recordings from tdTomato positive magnocellular neurons in the paraventricular nucleus of the hypothalamus revealed expected intrinsic properties, including transient outward rectification produced by a prominent A‐type K+ current (IA). Initial imaging studies revealed that the dendrites of OT positive magnocellular neurons are passive conductors, with robust activity dependent dendritic calcium influx that diminishes substantially with increasing distance from the soma. Bath application of an external osmolyte (15 mM mannitol) produced a clear increase in the frequency of spontaneous action potentials observed in OT positive magnocellular neurons, and yet intriguingly, also produced a clear decrease in activity dependent dendritic calcium influx. This effect was also much more prominent in distal dendrites than in proximal dendrites, consistent with a mechanism that depends on decreased dendritic input resistance. Also consistent with that interpretation, we found that acute application of 15 mM mannitol significantly reduces the amplitude of evoked glutamatergic EPSCs recorded at the soma, as produced by a small theta glass stimulator placed near the distal dendrites. Interestingly, preliminary data suggest that parvocellular OT neurons lack similar osmosensitivty. Collectively, these results provide a partial mechanistic explanation for why acute osmotic stress is likely to initially favor synaptic over paracrine release of OT from osmosensitive hypothalamic magnocellular neurons.

Support or Funding Information

Supported by NIMH R0104641

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.