Neuronal deletion of phosphatase and tensin homolog in mice results in spatial dysregulation of adult hippocampal neurogenesis.

Adult neurogenesis is a persistent phenomenon in mammals that occurs in select brain structures in both healthy and diseased brains. The tumor suppressor gene, phosphatase and tensin homolog deleted on chromosome 10 (Pten) has previously been found to restrict the proliferation of neural stem/progenitor cells (NSPCs) in vivo. In this study, we aimed to provide a comprehensive picture of how conditional deletion of Pten may regulate the genesis of adult NSPCs in the dentate gyrus of the hippocampus and the subventricular zone bordering the lateral ventricles. Using conventional markers and stereology, we quantified multiple stages of neurogenesis, including proliferating cells, immature neurons (neuroblasts), and apoptotic cells in several regions of the dentate gyrus, including the subgranular zone (SGZ), outer granule cell layer (oGCL), molecular layer, and hilus at 4 and 10 weeks of age. Our data demonstrate that conditional deletion of Pten in mice produces successive increases in dentate gyrus proliferating cells and immature neuroblasts, which confirms the known negative roles Pten has on cell proliferation and maturation. Specifically, we observe a significant increase in Ki67+ proliferating cells in the neurogenic SGZ at 4 weeks of age, but not 10 weeks of age. We also observe a delayed increase in neuroblasts at 10 weeks of age. However, our study expands on previous work by providing temporal, subregional, and neurogenesis-stage resolution. Specifically, we found that Pten deletion initially increases cell proliferation in the neurogenic SGZ, but this increase spreads to non-neurogenic dentate gyrus areas, including the hilus, oGCL, and molecular layer, as mice age. We also observed region-specific increases in apoptotic cells in the dentate gyrus hilar region that paralleled the regional increases in Ki67+ cells. Our work is accordant with the literature showing that Pten serves as a negative regulator of dentate gyrus neurogenesis but adds temporal and spatial components to the existing knowledge.

Rapamycin improves social and stereotypic behavior abnormalities induced by pre-mitotic neuronal subset specific Pten deletion.

The mechanistic target of rapamycin (mTOR) pathway is a signaling system integral to neural growth and migration. In both patients and rodent models, mutations to the phosphatase and tensin homolog gene (PTEN) on chromosome 10 results in hyperactivation of the mTOR pathway, as well as seizures, intellectual disabilities and autistic behaviors. Rapamycin, an inhibitor of mTOR, can reverse the epileptic phenotype of neural subset specific Pten knockout (NS-Pten KO) mice, but its impact on behavior is not known. To determine the behavioral effects of rapamycin, male and female NS-Pten KO and wildtype (WT) mice were assigned as controls or administered 10 mg/kg of rapamycin for 2 weeks followed by behavioral testing. Rapamycin improved social behavior in both genotypes and stereotypic behaviors in NS-Pten KO mice. Rapamycin treatment resulted in a reduction of several measures of activity in the open field test in both genotypes. Rapamycin did not reverse the reduced anxiety behavior in KO mice. These data show the potential clinical use of mTOR inhibitors by showing its administration can reduce the production of autistic-like behaviors in NS-Pten KO mice.

Assessment of the effects of sex, age, and rearing condition on ultrasonic vocalizations elicited by pups during the maternal potentiation paradigm in C57BL/6J mice.

Isolation-induced ultrasonic vocalizations (USVs) are important to elicit parental retrieval. This behavior is critical for the animal's survival and can be altered in models of developmental disorders. The potentiation of vocalizations in response to reunion with the dam, also called maternal potentiation, has been extensively studied in rats. However, the assessment of this paradigm in mice is scarce. In rats, the potentiation of vocalizations is dependent on rearing conditions. Since mice are the main species used for genetic models of diseases, we aimed to investigate how different factors such as age, sex, and rearing conditions can affect the potentiation of vocalizations in the maternal potentiation paradigm in mice. We carried out experiments using biparental (dam and sire) or uniparental rearing (dam). Pups were tested on postnatal days (PD) 9 or 12. Pups showed increased potentiation in both sexes at PD9 with uniparental rearing. Both rearing conditions and ages changed the repertoire from the first to the second isolation. Spectral parameters were affected by sex, rearing condition and reunion at PD9. At PD12, only duration was altered by reunion. We conclude that the performance of the pups in the maternal potentiation paradigm is dependent on age, sex, and rearing condition.