The Impact of Oxytocin on Neurite Outgrowth and Synaptic Proteins inMagel2-Deficient Mice

Abstract

Oxytocin contributes to the regulation of cytoskeletal and synaptic proteins and could therefore affect the mechanisms of neurodevelopmental disorders, including autism. Both the Prader-Willi syndrome and Schaaf-Yang syndrome exhibit autistic symptoms involving the MAGEL2 gene. Magel2-deficient mice show a deficit in social behavior that is rescued following postnatal administration of oxytocin. Here, in Magel2-deficient mice, we showed that the neurite outgrowth of primary cultures of immature hippocampal neurons is reduced. Treatment with oxytocin, but not retinoic acid, reversed this abnormality. In the hippocampus of Magel2-deficient pups, we further demonstrated that several transcripts of neurite outgrowth-associated proteins, synaptic vesicle proteins, and cell-adhesion molecules are decreased. In the juvenile stage, when neurons are mature, normalization or even overexpression of most of these markers was observed, suggesting a delay in the neuronal maturation of Magel2-deficient pups. Moreover, we found reduced transcripts of the excitatory postsynaptic marker, Psd95 in the hippocampus and we observed a decrease of PSD95/VGLUT2 colocalization in the hippocampal CA1 and CA3 regions in Magel2-deficient mice, indicating a defect in glutamatergic synapses. Postnatal administration of oxytocin upregulated postsynaptic transcripts in pups; however, it did not restore the level of markers of glutamatergic synapses in Magel2-deficient mice. Overall, Magel2 deficiency leads to abnormal neurite outgrowth and reduced glutamatergic synapses during development, suggesting abnormal neuronal maturation. Oxytocin stimulates the expression of numerous genes involved in neurite outgrowth and synapse formation in early development stages. Postnatal oxytocin administration has a strong effect in development that should be considered for certain neuropsychiatric conditions in infancy.

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

“…The hypothalamic neuropeptide OT has been in the focus of PWS research for more than two decades, even since the initial discovery by Swaab and colleagues, which reported a reduction in the number of OT cells within the PVN (10). Given the symptomatic overlap with ASD (56), a plethora of animal and human studies aimed to ameliorate behavioral symptoms via intranasal or systemic application of OT (6,7,(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) .…”

“…The hypothalamic neuropeptide OT has been in the focus of PWS research for more than two decades, even since the initial discovery by Swaab and colleagues, which reported a reduction in the number of OT cells within the PVN (10). Given the symptomatic overlap with ASD (56), a plethora of animal and human studies aimed to ameliorate behavioral symptoms via intranasal or systemic application of OT (6, 7, 12-23). However, information about the OTergic system in mouse models of PWS is still scarce and to date, no information about OTR-expressing astrocytes in Magel2 tm1 .…”

“…Swaab found that brains of individuals with PWS contained less OTergic neurons within the hypothalamus, especially in the caudal/posterior paraventricular nucleus (PVN) of the hypothalamus, where parvocellular OT (parvOT) neurons reside (11). In the years after Swaab's initial discovery, a multitude of studies deciphering the precise role of OT in PWS followed using both animal models and human patients (6,7,(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). One major study conducted in children with PWS highlighted that intranasal OT administration successfully restored suckling behavior (19) and a follow-up phase III trial of this experiment is currently underway NCT04283578.…”

Oxytocin-based therapies for treatment of Prader-Willi and Schaaf-Yang syndromes: evidence, disappointments, and future research strategies

“…Analysis of OT neurons in Magel2 tm1Stw mice revealed an overall suppressed activity of OT neurons resulting from an imbalance synaptic input onto OT neurons, characterized by reduced excitatory and increased inhibitory postsynaptic currents [ 59 ]. Furthermore, OT administration in Magel2 tm1.1Mus pups rescued several changes related to neurite outgrowth, including altered synaptic vesicle proteins and cell adhesion molecules [ 60 ]. Most importantly, however, based on the preclinical studies performed on Magel2 tm1.1Mus [ 54 ], one study investigated the effect of intranasal OT administration in infants with PWS and reported normalization of suckling in 88% of infants [ 61 ].…”

“…It seems plausible that OT cells innervate various socially-relevant brain regions less frequently, have impaired OT release from long-range axonal terminals and/or that a disease-driven downregulation of OTRs in different brain regions takes place. In fact, the findings that administration of OT during infancy rescued social recognition and learning disabilities until adulthood [ 20 , 21 ] and restored electrophysiological properties, normal levels of OTRs [ 20 ] and altered synaptic vesicle proteins and cell adhesion molecules in Magel2 KO mice [ 60 ] support this theory. However, to this date, no detailed study investigating the physiological, molecular or morphological changes in OT neurons in PWS/SYS has been conducted.…”