Neonatal Stimulation of PKC Epsilon Signaling Normalizes Fragile X-Associated Deficits in PVN Oxytocin Expression and Later-Life Social and Anxiety Behavior

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 (\u3eP60) 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

Pharmacological characterization of GABAA receptors in taurine-fed mice

<p>Abstract</p> <p>Background</p> <p>Taurine is one of the most abundant free amino acids especially in excitable tissues, with wide physiological actions. Chronic supplementation of taurine in drinking water to mice increases brain excitability mainly through alterations in the inhibitory GABAergic system. These changes include elevated expression level of glutamic acid decarboxylase (GAD) and increased levels of GABA. Additionally we reported that GABA_A receptors were down regulated with chronic administration of taurine. Here, we investigated pharmacologically the functional significance of decreased / or change in subunit composition of the GABA_A receptors by determining the threshold for picrotoxin-induced seizures. Picrotoxin, an antagonist of GABA_A receptors that blocks the channels while in the open state, binds within the pore of the channel between the β2 and β3 subunits. These are the same subunits to which GABA and presumably taurine binds.</p> <p>Methods</p> <p>Two-month-old male FVB/NJ mice were subcutaneously injected with picrotoxin (5 mg kg^-1) and observed for a) latency until seizures began, b) duration of seizures, and c) frequency of seizures. For taurine treatment, mice were either fed taurine in drinking water (0.05%) or injected (43 mg/kg) 15 min prior to picrotoxin injection.</p> <p>Results</p> <p>We found that taurine-fed mice are resistant to picrotoxin-induced seizures when compared to age-matched controls, as measured by increased latency to seizure, decreased occurrence of seizures and reduced mortality rate. In the picrotoxin-treated animals, latency and duration were significantly shorter than in taurine-treated animas. Injection of taurine 15 min before picrotoxin significantly delayed seizure onset, as did chronic administration of taurine in the diet. Further, taurine treatment significantly increased survival rates compared to the picrotoxin-treated mice.</p> <p>Conclusions</p> <p>We suggest that the elevated threshold for picrotoxin-induced seizures in taurine-fed mice is due to the reduced binding sites available for picrotoxin binding due to the reduced expression of the beta subunits of the GABA_A receptor. The delayed effects of picrotoxin after acute taurine injection may indicate that the two molecules are competing for the same binding site on the GABA_A receptor. Thus, taurine-fed mice have a functional alteration in the GABAergic system. These include: increased GAD expression, increased GABA levels, and changes in subunit composition of the GABA_A receptors. Such a finding is relevant in conditions where agonists of GABA_A receptors, such as anesthetics, are administered.</p