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.
Competing Interest Statement
The authors have declared no competing interest.
Abbreviations
- ASD
- autism spectrum disorder
- ATRA
- all-trans retinoic acid
- DIV
- day in vitro
- GABA
- γ-aminobutyric acid
- GAD
- glutamic acid decarboxylase
- GAP43
- growth associated protein 43
- GAPDH
- glyceraldehyde 3-phosphate dehydrogenase
- LIMK1
- LIM domain kinase 1
- MAGEL
- MAGE Family Member L2
- MAP2
- microtubule associated protein 2
- mTORC1
- mechanistic (or mammalian) target of rapamycin complex 1
- NLGN
- neuroligin
- NRXN
- neurexin
- OT
- oxytocin
- OXTR
- oxytocin receptors
- PAK1
- p21 activated kinase 1
- PSD95
- postsynaptic density protein 95
- PWS
- Prader–Willi Syndrome
- Rac1
- Ras-related C3 botulinum toxin substrate 1
- RhoA
- Ras homolog family member A
- RhoB
- Ras homolog family member B
- SHANK
- SH3 and multiple ankyrin repeat domains
- SYS
- Schaaf-Yang Syndrome
- TIAM1
- T-cell lymphoma invasion and metastasis 1
- TRIM27
- tripartite motif containing 27
- USP7
- ubiquitin specific peptidase 7
- VGLUT2
- vesicular glutamate transporter 2
- WASH
- Wiskott–Aldrich syndrome protein and SCAR homologue
- WT
- wild type