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: 15.05). 06/2006; 50(3):377-88. DOI: 10.1016/j.neuron.2006.03.023
Source: PubMed


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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    • "sely , enhanced mTOR signaling following inactivation of upstream negative regulators ( PTEN and TSC1 / 2 ) , or constitutive activation of positive regulators ( PI3K , Akt , and Ras ) , has been associated with macrocephaly , neuronal hypertrophy , and increased soma size and dendritic complexity of hippocampal neurons ( Jaworski et al . , 2005 ; Kwon et al . , 2006 ) . These effects of mTOR activation on neuronal and dendritic morphogenesis requires novel protein synthesis ( Jaworski et al . , 2005 ) . mTOR - mediated regulation of protein translation has garnered much interest in the field of ASD research . Substrates of mTOR that are critically involved in the translation initiation machinery , "
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    ABSTRACT: The genetic and phenotypic heterogeneity of autism spectrum disorders (ASD) presents a substantial challenge for diagnosis, classification, research, and treatment. Investigations into the underlying molecular etiology of ASD have often yielded mixed and at times opposing findings. Defining the molecular and biochemical underpinnings of heterogeneity in ASD is crucial to our understanding of the pathophysiological development of the disorder, and has the potential to assist in diagnosis and the rational design of clinical trials. In this review, we propose that genetically diverse forms of ASD may be usefully parsed into entities resulting from converse patterns of growth regulation at the molecular level, which lead to the correlates of general synaptic and neural overgrowth or undergrowth. Abnormal brain growth during development is a characteristic feature that has been observed both in children with autism and in mouse models of autism. We review evidence from syndromic and non-syndromic ASD to suggest that entities currently classified as autism may fundamentally differ by underlying pro- or anti-growth abnormalities in key biochemical pathways, giving rise to either excessive or reduced synaptic connectivity in affected brain regions. We posit that this classification strategy has the potential not only to aid research efforts, but also to ultimately facilitate early diagnosis and direct appropriate therapeutic interventions.
    Frontiers in Neuroscience 09/2015; 9. DOI:10.3389/fnins.2015.00313 · 3.66 Impact Factor
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    • "The key dependent measure was the ratio of time spent interacting with the stranger vs. empty cup in the familiarization stage or the novel vs. stranger mouse in the test stage. Normal, healthy mice show increased preference for the stranger mouse cup when compared to the empty cup, and the novel mouse cup when compared to the stranger mouse cup; preference for stranger vs. empty or novel vs. stranger is determined by a ratio >1 (Bevins & Besheer, 2006, Cohen & Stackman, in press, Kwon et al., 2006). 48 mice contributed data to the SNRT analysis: dys‐/dys‐ (n=10), dys‐/wt (n=12), wild‐type (n=14), and pallid mutant (n=11). "
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    ABSTRACT: Numerous studies have implicated DTNBP1, the gene encoding dystrobrevin-binding-protein or dysbindin, as a candidate risk gene for schizophrenia, though this relationship remains somewhat controversial. Variation in dysbindin, and its location on chromosome 6p, has been associated with cognitive processes, including those relying on a complex system of glutamatergic and dopaminergic interactions. Dysbindin is one of the 7 protein subunits that comprise the Biogenesis of Lysosome-related Organelles Complex 1 (BLOC-1). Dysbindin protein levels are lower in mice with null mutations in pallidin, another gene in the BLOC-1 complex, and pallidin levels are lower in mice with null mutations in the dysbindin gene, suggesting multiple subunit proteins must be present to form a functional oligomeric complex. Furthermore, pallidin and dysbindin have similar distribution patterns in a mouse and human brain. Here, we investigated whether the apparent correspondence of pallid and dysbindin at the level of gene expression is also found at the level of behavior. Hypothesizing a mutation leading to under-expression of either of these proteins should show similar phenotypic effects, we studied recognition memory in both strains using the Novel Object Recognition Task (NORT) and Social Novelty Recognition Task (SNRT). We found that mice with a null mutation in either gene are impaired on SNRT and NORT when compared to wild-type controls. These results support the conclusion that deficits consistent with recognition memory impairment, a cognitive function that is impaired in schizophrenia, result from either pallidin or dysbindin mutations, possibly through degradation of BLOC-1 complex expression and/or function. This article is protected by copyright. All rights reserved.
    Genes Brain and Behavior 08/2015; DOI:10.1111/gbb.12240 · 3.66 Impact Factor
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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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    ABSTRACT: The mechanistic target of rapamycin (mTOR) signaling pathway is a crucial cellular signaling hub that, like the nervous system itself, integrates internal and external cues to elicit critical outputs including growth control, protein synthesis, gene expression, and metabolic balance. The importance of mTOR signaling to brain function is underscored by the myriad disorders in which mTOR pathway dysfunction is implicated, such as autism, epilepsy, and neurodegenerative disorders. Pharmacological manipulation of mTOR signaling holds therapeutic promise and has entered clinical trials for several disorders. Here, we review the functions of mTOR signaling in the normal and pathological brain, highlighting ongoing efforts to translate our understanding of cellular physiology into direct medical benefit for neurological disorders.
    Neuron 10/2014; 84(2):275-291. DOI:10.1016/j.neuron.2014.09.034 · 15.05 Impact Factor
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