Article

Pten Regulates Neuronal Arborization and Social Interaction in Mice

Kent Waldrep Foundation Center for Basic Neuroscience Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Neuron (Impact Factor: 15.98). 06/2006; 50(3):377-88. DOI: 10.1016/j.neuron.2006.03.023
Source: PubMed

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.

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    • "Tsc1+/À and Tsc2+/À mice and the spontaneously haploinsufficient Tsc2+/À Eker rat demonstrate abnormal social interaction reversible by rapamycin treatment (Ehninger et al., 2008; Goorden et al., 2007; Sato et al., 2012; Waltereit et al., 2011). Forebrain-specific deletion of Pten also resulted in abnormal social behavior (Kwon et al., 2006). Deletion of Tsc1 or Tsc2 in cerebellar Purkinje cells resulted in marked abnormalities in social behavior, directly implicating mTOR signaling in the cerebellum as a mediator of social cognition (Reith et al., 2013; Tsai et al., 2012). "
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    Neuron 10/2014; 84(2):275-291. DOI:10.1016/j.neuron.2014.09.034 · 15.98 Impact Factor
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    • "Elevated anxiety is commonly associated with clinical ASD (Ozsivadjian and Knott, 2011; Simonoff et al., 2008). Many mouse models of autism display increased anxiety (Brodkin, 2007; Chahrour and Zoghbi, 2007; Kwon et al., 2006). In the KA-P7 ELS model, anxiety was not altered in the elevated plus maze (EPM) or open field test (OFT) (Cornejo et al., 2008; Stafstrom et al., 1993). "
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    • "Anomalies in dendritic morphology are observed in and contribute to the pathology of many neurodevelopmental and neurodegenerative disorders (Dierssen and Ramakers , 2006; Jan and Jan, 2010; Nestor and Hoffman, 2012). In particular, abnormal dendritic complexity is a shared feature of neurodevelopmental disorders associated with cognitive and social impairments, and altered tuberous sclerosis complexmammalian target of rapamycin (TSC-mTOR) signaling (Crino et al., 2006; Feliciano et al., 2013a; Kwiatkowski and Manning, 2005; Kwon et al., 2006). TSC is one such neurodevelopmental disorder. "
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    ABSTRACT: Abnormal dendritic complexity is a shared feature of many neurodevelopmental disorders associated with neurological defects. Here, we found that the actin-crosslinking protein filamin A (FLNA) is overex-pressed in tuberous sclerosis complex (TSC) mice, a PI3K-mTOR model of neurodevelopmental disease that is associated with abnormal dendritic com-plexity. Both under-and overexpression of FLNA in wild-type neurons led to more complex dendritic ar-bors in vivo, suggesting that an optimal level of FLNA expression is required for normal dendritogenesis. In Tsc1 null neurons, knocking down FLNA in vivo pre-vented dendritic abnormalities. Surprisingly, FLNA overexpression in Tsc1 null neurons was dependent on MEK1/2 but not mTOR activity, despite both path-ways being hyperactive. In addition, increasing MEK-ERK1/2 activity led to dendritic abnormalities via FLNA, and decreasing MEK-ERK1/2 signaling in Tsc1 null neurons rescued dendritic defects. These data demonstrate that altered FLNA expression increases dendritic complexity and contributes to pathologic dendritic patterning in TSC in an mTOR-independent, ERK1/2-dependent manner. INTRODUCTION
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