The extracellular signal-regulated kinase (ERK) pathway is critical for various forms of learning and memory, and is activated by the potent estrogen 17␤-estradiol (E 2 ). Here, we asked whether E 2 modulates memory via ERK activation and putative membrane-bound estrogen receptors (ERs). Using ovariectomized mice, we first demonstrate that intraperitoneal injection of 0.2 mg/kg E 2 significantly increases dorsal hippocampal levels of phosphorylated ERK protein 1 h after injection. Second, we show that E 2 administered intraperitoneally (0.2 mg/kg) or via intrahippocampal infusion (5.0 g/side) immediately after training in an object recognition task significantly enhances memory retention, and that the beneficial effect of intraperitoneal E 2 is blocked by dorsal hippocampal inhibition of ERK activation. Third, using bovine serum albumin-conjugated 17␤-estradiol (BSA-E 2 ), we demonstrate that E 2 binding at membrane-bound ERs can increase dorsal hippocampal ERK activation and enhance object memory consolidation in an ERK-dependent manner. Fourth, we show that this effect is independent of nuclear ERs, but is dependent on the dorsal hippocampus. By demonstrating that E 2 enhances memory consolidation via dorsal hippocampal ERK activation, this study is the first to identify a specific molecular pathway by which E 2 modulates memory and to demonstrate a novel role for membrane-bound ERs in mediating E 2 -induced improvements in hippocampal memory consolidation.

The mammalian target of rapamycin (mTOR) signaling pathway is an important regulator of protein synthesis and is essential for various forms of hippocampal memory. Here, we asked whether the enhancement of object recognition memory consolidation produced by dorsal hippocampal infusion of 17b-estradiol (E 2 ) is dependent on mTOR signaling in the dorsal hippocampus, and whether E 2 -induced mTOR signaling is dependent on dorsal hippocampal phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) activation. We first demonstrated that the enhancement of object recognition induced by E 2 was blocked by dorsal hippocampal inhibition of ERK, PI3K, or mTOR activation. We then showed that an increase in dorsal hippocampal ERK phosphorylation 5 min after intracerebroventricular (ICV) E 2 infusion was also blocked by dorsal hippocampal infusion of the three cell signaling inhibitors. Next, we found that ICV infusion of E 2 increased phosphorylation of the downstream mTOR targets S6K (Thr-421) and 4E-BP1 in the dorsal hippocampus 5 min after infusion, and that this phosphorylation was blocked by dorsal hippocampal infusion of inhibitors of ERK, PI3K, and mTOR. Collectively, these data demonstrate for the first time that activation of the dorsal hippocampal mTOR signaling pathway is necessary for E 2 to enhance object recognition memory consolidation and that E 2 -induced mTOR activation is dependent on upstream activation of ERK and PI3K signaling.The potent estrogen 17b-estradiol (E 2 ) is a critical regulator of hippocampal synaptic morphology. In rodents and nonhuman primates, E 2 increases hippocampal levels of synaptic proteins, including the presynaptic proteins synaptophysin and syntaxin, and the postsynaptic proteins spinophilin and PSD-95 (Brake et al.

Background Deletion of the recurrent ~600 kb BP4-BP5 chromosomal region 16p11.2 has been associated with a wide range of neurodevelopmental outcomes. Method To clarify the phenotype of 16p11.2 deletion, we examined psychiatric and developmental presentation of predominantly clinically referred individuals, with a particular emphasis on broader autism phenotype characteristics in individuals with recurrent ~600 kb chromosome 16p11.2 deletions. 85 Individuals with the 16p11.2 deletion, and 153 familial controls, were evaluated for symptom presentation and clinical diagnosis using an extensive standardized assessment battery across 3 clinical sites. Results Individuals with the 16p11.2 deletion presented with a high frequency of psychiatric and developmental disorders (>90%). The most commonly diagnosed conditions were developmental coordination disorder, phonological processing disorder, expressive and receptive language disorders (71% of individuals over 3 years of age with a speech and language related disorder), and autism spectrum disorder (ASD). Individuals with the 16p11.2 deletion not meeting diagnostic criteria for ASD had significantly higher prevalence of autism-related characteristics compared to the familial non-carrier control group. Individuals with the 16p11.2 deletion had a range of intellectual ability, but IQ scores were 26 points lower than non-carrier family members on average. Conclusion Clinically referred individuals with the 16p11.2 deletion have high rates of psychiatric and developmental disorders and provide a genetically well-defined group to study the emergence of developmental difficulties, particularly those associated with the broader autism phenotype.

We previously demonstrated that dorsal hippocampal extracellular signal-regulated kinase (ERK) activation is necessary for 17␤-estradiol (E 2 ) to enhance novel object recognition in young ovariectomized mice (Fernandez et al., 2008). Here, we asked whether E 2 has similar memory-enhancing effects in middle-aged and aged ovariectomized mice, and whether these effects depend on ERK and phosphatidylinositol 3-kinase (PI3K)/Akt activation. We first demonstrated that intracerebroventricular or intrahippocampal E 2 infusion immediately after object recognition training enhanced memory consolidation in middle-aged, but not aged, females. The E 2 -induced enhancement in middle-aged females was blocked by intrahippocampal inhibition of ERK or PI3K activation. Intrahippocampal or intracerebroventricular E 2 infusion in middle-aged females increased phosphorylation of p42 ERK in the dorsal hippocampus 15 min, but not 5 min, after infusion, an effect that was blocked by intrahippocampal inhibition of ERK or PI3K activation. Dorsal hippocampal PI3K and Akt phosphorylation was increased 5 min after intrahippocampal or intracerebroventricular E 2 infusion in middle-aged, but not aged, females. Intracerebroventricular E 2 infusion also increased PI3K phosphorylation after 15 min, and this effect was blocked by intrahippocampal PI3K, but not ERK, inhibition. These data demonstrate for the first time that activation of dorsal hippocampal PI3K/ Akt and ERK signaling pathways is necessary for E 2 to enhance object recognition memory in middle-aged females. They also reveal that similar dorsal hippocampal signaling pathways mediate E 2 -induced object recognition memory enhancement in young and middle-aged females and that the inability of E 2 to activate these pathways may underlie its failure to enhance object recognition in aged females.