Date of Degree
Behavioral Neurobiology | Developmental Neuroscience | Molecular and Cellular Neuroscience
fragile x syndrome, hippocampus, hypothalamus, oxytocin, brain development
Fragile X Syndrome (FXS) is an inherited developmental disorder characterized by disturbances in emotional and social behavior. Our studies have revealed suppressed hippocampal PKCε expression in Fmr1 knockout (KO) mice, the leading model of FXS. To compensate for this deficiency, we stimulated PKCε in neonatal KO mice by administering a selective PKCε activator, dicyclopropyl-linoleic acid (DCP-LA), and studied its effect on ventral hippocampal neurons and a proximal target of the ventral hippocampus, the hypothalamus, which regulates social and emotional behavior. We observed that at postnatal day 18 (P18), vehicle-treated KO mice displayed increased surface localization of the 3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR2 in the ventral CA1 region, indicative of increased neuronal excitability. Since the hippocampus is known to exert an inhibitory influence on the hypothalamus, we tested if this possible CA1 stimulation was associated with a suppression of oxytocin synthesis in the hypothalamus. Intriguingly, the number of oxytocin+ cells in the hypothalamic paraventricular nucleus (PVN) of P20 KO mice was sharply suppressed. However, both the increased surface localization of GluR2 and the suppression of PVN oxytocin+ cells in the KO mice were rescued by DCP-LA treatment from P6-14, to levels comparable to that in the wild-type controls. Moreover, this neonatal treatment regimen was able to fully rescue hyper-anxiety and social behavior deficits in adult (>P60) KO mice. Thus, we present a novel strategy to circumvent aberrant brain development in FXS and accompanying behavioral deficits, by activating PKCε signaling during neonatal development.
Marsillo, Alexandra E., "Neonatal Stimulation of PKC Epsilon Signaling Normalizes Fragile X-Associated Deficits in PVN Oxytocin Expression and Later-Life Social and Anxiety Behavior" (2018). CUNY Academic Works.