Analysis of the hypothalamic oxytocin system and oxytocin receptor-expressing astrocytes in a mouse model of Prader-Willi syndrome

Abstract

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by hyperphagia, obesity, developmental delay and intellectual disability. Studies suggest dysfunctional signaling of the neuropeptide oxytocin as one of the key mechanisms in PWS, and administration of oxytocin via intranasal or systemic routes yielded promising results in both humans and mouse models. However, a detailed assessment of the oxytocin system in mouse models of PWS such as the Magel2-deficient Magel2tm1.Stw mouse, is lacking. In this study, we performed an automated counting of oxytocin cells in the entire paraventricular nucleus of the hypothalamus of Magel2tm1.Stw and wild-type control mice and found a significant reduction in the caudal part, which represents the parvocellular subdivision. In addition, based on the recent discovery that some astrocytes express the oxytocin receptor (OTR), we performed detailed analysis of astrocyte numbers and morphology in various brain regions, and assessed expression levels of the astrocyte marker GFAP, which was significantly decreased in the hypothalamus, but not other brain regions in Magel2tm1.Stw mice. Finally, we analyzed the number of OTR-expressing astrocytes in various brain regions and found a significant reduction in the nucleus accumbens of Magel2tm1.Stw mice, as well as a sex-specific difference in the lateral septum. This study suggests a role for caudal PVN OT neurons as well as OTR-expressing astrocytes in a mouse model of PWS, provides novel information about sex-specific expression of astrocytic OTRs, and presents several new brain regions containing OTR-expressing astrocytes in the mouse brain.

Heralding a new era of oxytocinergic research: New tools, new problems?

“…Albeit the presence of OTRs on glial cells has been described before, 26,27 their respective role was deemed insignificant or at least, not studied. However, this dogmatic view has recently been challenged and it became evident that physiologically and behaviorally‐relevant populations of OTR‐expressing astrocytes exist in various brain regions of mouse and rat 12,28–32 . In their original publication, Wahis and colleagues demonstrated the existence of strategically‐positioned and morphologically distinct population of OTR‐positive astrocytes in the central amygdala, which modulates comfort, anxiety and pain by orchestrating the activity of neurons within the central amygdala 31 .…”

“…However, this dogmatic view has recently been challenged and it became evident that physiologically and behaviorally-relevant populations of OTR-expressing astrocytes exist in various brain regions of mouse and rat. 12,[28][29][30][31][32] In their original publication, Wahis and colleagues demonstrated the existence of strategically-positioned and morphologically distinct population of OTR-positive astrocytes in the central amygdala, which modulates comfort, anxiety and pain by orchestrating the activity of neurons within the central amygdala. 31 Intriguingly, they observed that OTRmediated activation of astrocytes preceded neuronal activation and inhibition of astrocytic OTRs almost entirely blocks the functionality of the local neuronal central amygdala microcircuit.…”