A seizure-prone phenotype is associated with altered free-running rhythm in Pten mutant mice

Ogawa, Shiori; Kwon, Chil Hun; Zhou, Jing; Koovakkattu, Della; Parada, Luis F.; Sinton, Christopher M.

doi:10.1016/j.brainres.2007.06.074

Cited by 78 publications

(64 citation statements)

References 59 publications

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“…The Pten m3m4 model also demonstrated poor balance on the accelerating rotarod task, potentially in keeping with the motor clumsiness reported in individuals with high-functioning ASD [61,89]. Finally, altered circadian rhythms are noted in ASD, and are also reported in the Nse-cre; Pten loxP/loxP model as disturbed free-running rhythm and lower overall circadian activity in female Pten +/-mice [84,86].…”

Section: Autism-like Behavioral Phenotypes In Mouse Models Of Pten Losupporting

confidence: 55%

Balancing Proliferation and Connectivity in PTEN-associated Autism Spectrum Disorder

2015

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Germline mutations in PTEN, which encodes a widely expressed phosphatase, was mapped to 10q23 and identified as the susceptibility gene for Cowden syndrome, characterized by macrocephaly and high risks of breast, thyroid, and other cancers. The phenotypic spectrum of PTEN mutations expanded to include autism with macrocephaly only 10 years ago. Neurological studies of patients with PTENassociated autism spectrum disorder (ASD) show increases in cortical white matter and a distinctive cognitive profile, including delayed language development with poor working memory and processing speed. Once a germline PTEN mutation is found, and a diagnosis of phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome made, the clinical outlook broadens to include higher lifetime risks for multiple cancers, beginning in childhood with thyroid cancer. First described as a tumor suppressor, PTEN is a major negative regulator of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) signaling pathway-controlling growth, protein synthesis, and proliferation. This canonical function combines with less well-understood mechanisms to influence synaptic plasticity and neuronal cytoarchitecture. Several excellent mouse models of Pten loss or dysfunction link these neural functions to autism-like behavioral abnormalities, such as altered sociability, repetitive behaviors, and phenotypes like anxiety that are often associated with ASD in humans. These models also show the promise of mTOR inhibitors as therapeutic agents capable of reversing phenotypes ranging from overgrowth to low social behavior. Based on these findings, therapeutic options for patients with PTEN hamartoma tumor syndrome and ASD are coming into view, even as new discoveries in PTEN biology add complexity to our understanding of this master regulator.

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Section: Autism-like Behavioral Phenotypes In Mouse Models Of Pten Losupporting

confidence: 55%

Balancing Proliferation and Connectivity in PTEN-associated Autism Spectrum Disorder

2015

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“…In our previous study, we used Nse-Cre to delete PTEN in mature neurons of cerebral cortex as well as the dentate gyrus and CA3 region of the hippocampus (Kwon et al, 2006;Ogawa et al, 2007). The Pten-deficient mice displayed deficiencies in classic social interaction paradigms designed to test autism-like behavior in mice (Crawley, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Pten was deleted in a subset of postmitotic neurons in the cortex and hippocampus have deficits in social activity, learning, reaction to sensory stimuli, anxiety-like behaviors, and sporadic seizures, which are all features associated with human ASDs (Kwon et al, 2006;Ogawa et al, 2007). Therefore, we were interested to see whether deleting Pten specifically in SGZ and SVZ adult NSCs, without cortical or CA3 involvement, would result in similar defects.…”

Section: Behavioral Defectsmentioning

confidence: 99%

“…Deletion of Pten in mature neuronal populations in the cerebral cortex and hippocampus resulted in macrocephaly, abnormal dendritic and axonal growth and synapse number. These mice also showed behavioral abnormalities resembling certain features of human ASDs (Kwon et al, 2006;Ogawa et al, 2007). Mouse models based on Pten deletion in the brain have also provided information about the role of Pten in neural stem/progenitor cell (NSC) proliferation and self-renewal (Groszer et al, 2001;Gregorian et al, 2009).…”

Section: Introductionmentioning

confidence: 97%

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

et al. 2012

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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.

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“…The mTOR pathway is activated in several models of epilepsy (Zeng et al , 2009; Huang et al, 2010; Okamoto et al, 2010; Zhang and Wong, 2012) and the mTOR blocker rapamycin has anti-epileptogenic properties (Zeng et al , 2009; Huang et al ., 2010) and inhibits mossy fiber sprouting (Buckmaster et al ., 2009; Buckmaster and Lew, 2011). Conversely, hyperactivation of the mTOR pathway by deleting phosphatase and tensin homologue (PTEN) is epileptogenic (Backman et al , 2001; Ogawa et al , 2007; Ljungberg et al, 2009). PTEN is a lipid phosphatase which targets the 3′ phosphate of phosphatidylinositol 3,4,5 triphosphate, thus acting in opposition to phosphatidylinositol 3-kinase (PI3K).…”

Section: Introductionmentioning

confidence: 99%

Excessive Activation of mTOR in Postnatally Generated Granule Cells Is Sufficient to Cause Epilepsy

Pun

Rolle

LaSarge

et al. 2012

Neuron

233

263

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Summary The dentate gyrus is hypothesized to function as a “gate”, limiting the flow of excitation through the hippocampus. During epileptogenesis, adult-generated granule cells (DGC) form aberrant neuronal connections with neighboring DGC, disrupting the dentate gate. Hyperactivation of the mTOR signaling pathway is implicated in driving this aberrant circuit formation. While the presence of abnormal DGC in epilepsy has been known for decades, direct evidence linking abnormal DGC to seizures has been lacking. Here, we isolate the effects of abnormal DGC using a transgenic mouse model to selectively delete PTEN from postnatally-generated DGC. PTEN deletion led to hyperactivation of the mTOR pathway, producing abnormal DGC morphologically similar to those in epilepsy. Strikingly, animals in which PTEN was deleted from ≥9% of the DGC population developed spontaneous seizures in about four weeks, confirming that abnormal DGC – which are present in both animals and humans with epilepsy – are capable of causing the disease.

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A seizure-prone phenotype is associated with altered free-running rhythm in Pten mutant mice

Cited by 78 publications

References 59 publications

Balancing Proliferation and Connectivity in PTEN-associated Autism Spectrum Disorder

Balancing Proliferation and Connectivity in PTEN-associated Autism Spectrum Disorder

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

Excessive Activation of mTOR in Postnatally Generated Granule Cells Is Sufficient to Cause Epilepsy

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