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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Available from: Bryan W Luikart, Feb 02, 2016
    • "Mouse models with PTEN germline haploinsufficiency show deficits in sociability and increased repetitive behavior, along with brain overgrowth (Clipperton-Allen and Page, 2014, 2015). Conditional knockout mice with PTEN deletion in neurons of the cerebral cortex and hippocampus develop macrocephaly due to neuronal hypertrophy and show behavioral abnormalities reminiscent of ASDs (Kwon et al, 2006). "
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    ABSTRACT: Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by impaired social interaction, isolated areas of interest and insistence on sameness. Mutations in Phosphatase and tensin homolog missing on chromosome 10 (PTEN) have been reported in individuals with ASDs. Recent evidence highlights a crucial role of the cerebellum in the etiopathogenesis of ASDs. In the present study we analyzed the specific contribution of cerebellar Purkinje cell (PC) PTEN loss to these disorders. Using the Cre-loxP recombination system, we generated conditional knockout mice in which PTEN inactivation was induced specifically in PCs. We investigated PC morphology and physiology as well as sociability, repetitive behavior, motor learning and cognitive inflexibility of adult PC PTEN mutant mice. Loss of PTEN in PCs results in autistic-like traits, including impaired sociability, repetitive behavior and deficits in motor learning. Mutant PCs appear hypertrophic and show structural abnormalities in dendrites and axons, decreased excitability, disrupted parallel fiber and climbing fiber synapses and late-onset cell death. Our results unveil new roles of PTEN in PC function and provide the first evidence of a link between the loss of PTEN in PCs and the genesis of ASD-like traits.Neuropsychopharmacology accepted article preview online, 05 November 2015. doi:10.1038/npp.2015.339.
    No preview · Article · Nov 2015 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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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.
    Full-text · Article · Sep 2015 · Frontiers in Neuroscience
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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.
    Full-text · Article · Aug 2015 · Genes Brain and Behavior
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