Pten Regulates Neuronal Arborization and Social Interaction in Mice

Abstract

CNS deletion of Pten in the mouse has revealed its roles in controlling cell size and number, thus providing compelling etiology for macrocephaly and Lhermitte-Duclos disease. PTEN mutations in individuals with autism spectrum disorders (ASD) have also been reported, although a causal link between PTEN and ASD remains unclear. In the present study, we deleted Pten in limited differentiated neuronal populations in the cerebral cortex and hippocampus of mice. Resulting mutant mice showed abnormal social interaction and exaggerated responses to sensory stimuli. We observed macrocephaly and neuronal hypertrophy, including hypertrophic and ectopic dendrites and axonal tracts with increased synapses. This abnormal morphology was associated with activation of the Akt/mTor/S6k pathway and inactivation of Gsk3beta. Thus, our data suggest that abnormal activation of the PI3K/AKT pathway in specific neuronal populations can underlie macrocephaly and behavioral abnormalities reminiscent of certain features of human ASD.

Advances in behavioral genetics: mouse models of autism

“…212 A recently reported genetic mouse model for autism is based on disruption of Pten in post-mitotic neurons of the cerebral cortex and dentate gyrus. 213 Germline mutation of Pten results in embryonic lethality at embryonic day 9.5 due to defective chorioallantoic development; embryos also have expanded and poorly patterned cephalic and caudal regions. 214 However, early mortality is not observed with neuron-specific ablation of Pten using Nse-cre.…”

“…214 However, early mortality is not observed with neuron-specific ablation of Pten using Nse-cre. 213 These animals exhibit low social approach, increased activity in a novel environment and impaired sensorimotor gating. Brains from conditional Pten-null mice show progressive macrocephaly, which may reflect the larger head circumference reported in autistic children.…”

“…176 On a neuronal level, there is dendritic hypertrophy, ectopic dendrites and increased spine density. 213 PTEN acts as a phosphatase on phosphatidylinositol triphosphate to antagonize signaling through the PI3K pathway. 215 This pathway (in blue; Figure 1) has an important role in protein synthesis, as well as in the regulation of cell size and proliferation.…”

NS‐Pten knockout mice show sex‐ and age‐specific differences in ultrasonic vocalizations

“…The NS‐ Pten mice used were on a FVB‐based backcrossed background strain that had been bred for more than 10 generations and have been previously described (RRID:MGI:3714016) (Kwon et al., 2006). NS‐ Pten loxP /+  heterozygote parents were bred and used to produce NS‐ Pten +/+  wild‐type (WT), NS‐ Pten loxP /+  heterozygous (HT), and NS‐ Pten loxP /loxP KO pups.…”

“…However, one common factor that has been observed in many of the single‐gene mutation syndrome disorders, such as Fragile X, Tuberous sclerosis, and Cowden syndrome, is hyperactivation of the PI3K/Akt/mTOR intracellular signaling pathway (Amir et al., 1999; Baker, Piven, & Sato, 1998; Hatton et al., 2006; Matsuura et al., 1997). Mutations of the suppressors of the pathway, TSC1 , TSC2 , or PTEN in mice, produce uncontrolled activation of the mTORC1 signaling cascade that results in macrocephaly and overgrowth in cellular and dendritic properties (Kwon et al., 2006; Meikle et al., 2008; Zeng, Xu, Gutmann, & Wong, 2008; Zhou et al., 2009). The Phosphoinositide 3‐kinase (PI3K) signaling cascade is activated by nutrients, growth factors and hormones, and is inhibited by PTEN (phosphatase and tensin homolog on chromosome 10).…”