Correction: Genetic risk for schizophrenia and psychosis in Alzheimer disease.

A number of collaborators were not acknowledged for their contribution to this published article. The acknowledgements that were missing in this published article can now be found in the associated correction.

Genetic risk for schizophrenia and psychosis in Alzheimer disease.

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD), affecting ~40 to 60% of individuals with AD (AD with psychosis (AD+P)). In comparison with AD subjects without psychosis, AD+P subjects have more rapid cognitive decline and poor outcomes. Prior studies have estimated the heritability of psychosis in AD at 61%, but the underlying genetic sources of this risk are not known. We evaluated a Discovery Cohort of 2876 AD subjects with (N=1761) or without psychosis (N=1115). All subjects were genotyped using a custom genotyping array designed to evaluate single-nucleotide polymorphisms (SNPs) with evidence of genetic association with AD+P and include SNPs affecting or putatively affecting risk for schizophrenia and AD. Results were replicated in an independent cohort of 2194 AD subjects with (N=734) or without psychosis (N=1460). We found that AD+P is associated with polygenic risk for a set of novel loci and inversely associated with polygenic risk for schizophrenia. Among the biologic pathways identified by the associations of schizophrenia SNPs with AD+P are endosomal trafficking, autophagy and calcium channel signaling. To the best of our knowledge, these findings provide the first clear demonstration that AD+P is associated with common genetic variation. In addition, they provide an unbiased link between polygenic risk for schizophrenia and a lower risk of psychosis in AD. This provides an opportunity to leverage progress made in identifying the biologic effects of schizophrenia alleles to identify novel mechanisms protecting against more rapid cognitive decline and psychosis risk in AD.

The duration of estradiol and progesterone exposure prior to progesterone withdrawal regulates oxytocin mRNA levels in the paraventricular nucleus of the rat.

The nonapeptide oxytocin (OT) is important for milk ejection during lactation, uterine contractility at parturition, and the onset of maternal behavior. Sequential exposure to estradiol (E2) and progesterone (P) followed by P withdrawal increases OT mRNA in the paraventricular nucleus (PVN), and to a lesser degree the supraoptic nucleus (SON), of the rat 48 hours after the P is removed. Although increases in PVN OT mRNA are not accompanied by changes in posterior pituitary OT peptide content, the PVN contains OT neurons that project to both the posterior pituitary (magnocellular group) and extra pituitary sites (parvocellular groups). Steroid-induced increases in OT mRNA occur in both the magnocellular and the parvocellular regions of the PVN. The latter are believed to contribute to CNS release of OT which may be important for certain behaviors including the onset of maternal behavior. The same steroid sequence that increases PVN OT mRNA also induces maternal behavior in virgin ovariectomized rats. Exposure of animals to E2 and P for 2 weeks resulted in the shortest latency to the onset of maternal behavior in ovariectomized rats, whereas exposure for 6 days was associated with a longer latency. In this study we questioned if the duration of E2 and P exposure prior to P withdrawal is an important regulator of PVN OT mRNA levels. We compared OT mRNA levels in the PVN of virgin ovariectomized rats administered no steroid or sequential E2 and P for 2 weeks versus 6 days. On day 1 animals received steroid-filled or empty capsules followed by P-filled or empty capsules on day 3. In one steroid-treated group, E2 and P were continued for 6 days and in the other group for 14 days prior to P removal. Animals were sacrificed 48 hours after P removal. Levels of OT mRNA were compared among 6 day and 2 week steroid-treated animals and sham-treated animals. The relative abundance of OT mRNA was significantly increased, P < 0.05, in animals receiving the 2-week, but not the 6-day, steroid treatment compared to sham-treated animals. Pituitary OT peptide content was not significantly different among the three groups. We conclude that the duration of steroid exposure may be an important regulator of the level of OT mRNA in the PVN of the rat.

Administration of long-term estradiol and progesterone followed by progesterone withdrawal does not alter the plasma oxytocin secretory response to cholecystokinin or the pituitary oxytocin content in ovariectomized rats.

The hormone oxytocin (OT) is important for several pre- and postpartum events, including uterine contractions at parturition, the induction of maternal behavior, and milk ejection during nursing. During late pregnancy, OT mRNA is increased in the paraventricular nucleus (PVN) due to high estrogen and declining progesterone levels. Administration of sequential estrogen and progesterone to, followed by withdrawal of progesterone from, an ovariectomized rat also increases OT mRNA. However, pituitary OT peptide is not affected. In the present experiment, we determined if this steroid exposure alters peripheral OT secretion during a provocative stimulus to OT release, such as cholecystokinin (CCK). Adult ovariectomized Sprague-Dawley rats were implanted on day 1 with either estrogen or empty silastic capsules, on day 3 with progesterone or empty capsules, and on day 14 progesterone or empty capsules were removed. Forty-eight hrs after removal of the progesterone capsules, plasma OT was measured before and after i.v. injection of 10 micrograms/kg of CCK. At the completion of the study, pituitary glands were removed and OT peptide was measured. No significant differences were found between the sham and hormone-treated animals either in their basal or CCK-stimulated plasma OT levels or their pituitary content of OT peptide. Although sequential exposure to estradiol and progesterone followed by withdrawal of progesterone has been shown previously to increase PVN OT mRNA, neither pituitary OT immunoreactivity nor basal and CCK-stimulated release of plasma OT is affected by this treatment. Although the mechanism of this steroid effect is not yet understood, our observations suggest a unique action of gonadal steroids upon PVN OT neurons.

Time course of induction of oxytocin messenger ribonucleic acid levels in the hypothalamic paraventricular nucleus of ovariectomized rats following gonadal steroid administration.

The nonapeptide oxytocin (OT) is important for uterine contractility at parturition, milk ejection during lactation, and the induction of maternal behavior. OT messenger ribonucleic acid (mRNA) levels increase in the paraventricular and supraoptic nuclei (PVN and SON) of late pregnant and lactating rats and are modulated by the steroid milieu that accompanies these states. Specifically, sequential exposure to estradiol (E2) and progesterone (P) followed by P withdrawal 48 hrs prior to sacrifice increases PVN, and to a lesser but significant degree, SON OT mRNA. To better define the time course of induction of OT mRNA levels following P withdrawal, ovariectomized Sprague-Dawley rats were treated with empty or steroid-filled capsules. On day 1, animals received an E2-filled or empty capsule, followed by P-filled or empty capsules on day 3. On day 14, P-filled or empty capsules were removed and animals were sacrificed 24, 36, or 48 hrs later. The hypothalamic PVN were analyzed for OT mRNA by in situ hybridization histochemistry. Significant differences in PVN OT mRNA were found among the groups (P<0.0001, Kruskal-Wallis). Animals in the 48 hr (P=0.007) and 36 hr (P=0.005), but not the 24 hr, steroid-treated groups had significantly increased OT mRNA relative to their respective sham-treated cohorts (Mann-Whitney U test). The relative abundance of PVN OT mRNA differed among the steroid-treated groups (Kruskal-Wallis, P<0.0003), with highest levels at 48 hr. We conclude that increases in PVN OT mRNA occur by 36 hrs, and are highest at 48 hrs, after P withdrawal in the E2-primed rat. Future studies will determine if OT-mediated changes in behavior or physiology that surround parturition are related to these changes in OT mRNA.