PtenDeletion in Adult Hippocampal Neural Stem/Progenitor Cells Causes Cellular Abnormalities and Alters Neurogenesis

Abstract

Adult neurogenesis persists throughout life in restricted brain regions in mammals and is affected by various physiological and pathological conditions. The tumor suppressor gene Pten is involved in adult neurogenesis and is mutated in a subset of autism patients with macrocephaly; however, the link between the role of PTEN in adult neurogenesis and the etiology of autism has not been studied before. Moreover, the role of hippocampus, one of the brain regions where adult neurogenesis occurs, in development of autism is not clear. Here, we show that ablating Pten in adult neural stem cells in the subgranular zone of hippocampal dentate gyrus results in higher proliferation rate and accelerated differentiation of the stem/progenitor cells, leading to depletion of the neural stem cell pool and increased differentiation toward the astrocytic lineage at later stages. Pten-deleted stem/progenitor cells develop into hypertrophied neurons with abnormal polarity. Additionally, Pten mutant mice have macrocephaly and exhibit impairment in social interactions and seizure activity. Our data reveal a novel function for PTEN in adult hippocampal neurogenesis and indicate a role in the pathogenesis of abnormal social behaviors.

Balancing Proliferation and Connectivity in PTEN-associated Autism Spectrum Disorder

“…Compared with wild-type mice, the first model to demonstrate reduced social behavior was the Nse-cre; Pten loxP/loxP mouse, which showed a reduced preference for another mouse than a nonsocial object [62]. This decrease in social behavior was replicated in later models based on Pten loss in more restricted populations, such as granule cells of the dentate gyrus and cerebellum or neural progenitors in adult animals [67,87]. Having established the critical role of neuronal Pten activity for normal social behavior, other models add context for what may occur in PHTS where PTEN mutations are germline and behavioral phenotypes are the collective expression of this pathology in every cell type.…”

“…Pten heterozygous animals are viable, and along with the differentiated neuronrestricted model Nse-cre;Pten loxP/loxP , represent the best phenotyped models for Pten loss in the CNS [62,66]. Extending findings from these earlier models, second generations of Pten cKOs with more restricted Pten loss were used to pinpoint the minimal cell types and time points required for normal behavioral and synaptic development [67,68]. While neuronal models have the most complete phenotyping for ASD-like deficits, the emergence of glial gene expression signatures in studies of neural tissue from individuals with ASD prompts further consideration of roles for PTEN in astrocytes and oligodendrocytes as well [69].…”

“…The effect is particularly striking in progenitor populations, which must balance renewal of the stem population with the generation of fate-restricted daughter cells [67]. In the Nestin-CreER T2 mouse, Pten loss in neural progenitors caused a burst of proliferation and generation of new neurons.…”

“…In the Nestin-CreER T2 mouse, Pten loss in neural progenitors caused a burst of proliferation and generation of new neurons. This increase was followed by early terminal differentiation that was skewed toward the astrocytic lineage [67]. In the Pten m3m4 model, disruption of Pten localization toward cytoplasmic predominance led to a substantial increase in neural/ glial antigen 2-positive polydendrocyte proliferation accompanied by greater numbers of astrocytes and oligodendrocytes, without affecting the density of neurons or microglia [61].…”

Regulation of Recombination and Genomic Maintenance

“…Importantly, PTEN is associated with a subset of individuals with autism spectrum disorders (Butler et al 2005;Varga et al 2009;McBride et al 2010). This may be related to the function of PTEN in neuronal stem cells (Amiri et al 2012). It is unknown what role HR plays in neuronal stem-cell development, and HR-deficient viable mice have not been tested for neurodevelopmental defects.…”