Rapamycin suppresses seizures and neuronal hypertrophy in a mouse model of cortical dysplasia

The Cain Foundation Laboratories, Texas Children's Hospital, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Disease Models and Mechanisms (Impact Factor: 4.97). 06/2009; 2(7-8):389-98. DOI: 10.1242/dmm.002386
Source: PubMed


Malformations of the cerebral cortex known as cortical dysplasia account for the majority of cases of intractable childhood epilepsy. With the exception of the tuberous sclerosis complex, the molecular basis of most types of cortical dysplasia is completely unknown. Currently, there are no good animal models available that recapitulate key features of the disease, such as structural cortical abnormalities and seizures, hindering progress in understanding and treating cortical dysplasia. At the neuroanatomical level, cortical abnormalities may include dyslamination and the presence of abnormal cell types, such as enlarged and misoriented neurons and neuroglial cells. Recent studies in resected human brain tissue suggested that a misregulation of the PI3K (phosphoinositide 3-kinase)-Akt-mTOR (mammalian target of rapamycin) signaling pathway might be responsible for the excessive growth of dysplastic cells in this disease. Here, we characterize neuronal subset (NS)-Pten mutant mice as an animal model of cortical dysplasia. In these mice, the Pten gene, which encodes a suppressor of the PI3K pathway, was selectively disrupted in a subset of neurons by using Cre-loxP technology. Our data indicate that these mutant mice, like cortical dysplasia patients, exhibit enlarged cortical neurons with increased mTOR activity, and abnormal electroencephalographic activity with spontaneous seizures. We also demonstrate that a short-term treatment with the mTOR inhibitor rapamycin strongly suppresses the severity and the duration of the seizure activity. These findings support the possibility that this drug may be developed as a novel antiepileptic treatment for patients with cortical dysplasia and similar disorders.

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    • "The growth-promoting Akt/mTor signaling cascade is also a hub for other ASD candidate genes, including Tsc1 and Tsc2 (Wiznitzer 2004) and NF1 (Marui et al., 2004; Mbarek et al., 1999). Pten is broadly expressed in the developing and adult mouse brain, including in glutamatergic and GABAergic neurons (herein and Ljungberg et al., 2009). Pten regulates many developmental processes, including migration (Kö lsch et al., 2008), growth and morphogenesis (Kwon et al., 2006), and synaptic dynamics (Fraser et al., 2008; Luikart et al., 2011; Williams et al., 2015). "
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    ABSTRACT: Mutations in the phosphatase PTEN are strongly implicated in autism spectrum disorder (ASD). Here, we investigate the function of Pten in cortical GABAergic neurons using conditional mutagenesis in mice. Loss of Pten results in a preferential loss of SST(+) interneurons, which increases the ratio of parvalbumin/somatostatin (PV/SST) interneurons, ectopic PV(+) projections in layer I, and inhibition onto glutamatergic cortical neurons. Pten mutant mice exhibit deficits in social behavior and changes in electroencephalogram (EEG) power. Using medial ganglionic eminence (MGE) transplantation, we test for cell-autonomous functional differences between human PTEN wild-type (WT) and ASD alleles. The PTEN ASD alleles are hypomorphic in regulating cell size and the PV/SST ratio in comparison to WT PTEN. This MGE transplantation/complementation assay is efficient and is generally applicable for functional testing of ASD alleles in vivo. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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    • "The importance of the mTORC1 signaling pathway and its regulation by PTEN are apparent in the cellular hypertrophy that results from PTEN loss (Backman et al., 2001). This effect is reversed in neurons by inhibitors of mTOR kinase activity (Kwon et al., 2003; Ljungberg et al., 2009; Zhou et al., 2009). Similar hypertrophy is also observed in astrocytes (Fraser et al., 2004), but there is some indication that this phenotype may be sensitive to the timing of PTEN loss. "
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    ABSTRACT: This review will consider the impact of compromised PTEN signaling in brain patterning. We approach understanding the contribution of PTEN to nervous system development by surveying the findings from the numerous genetic loss-of-function models that have been generated as well as other forms of PTEN inactivation. By exploring the developmental programs influenced by this central transduction molecule, we can begin to understand the molecular mechanisms that shape the developing brain. A wealth of data indicates that PTEN plays critical roles in a variety of stages during brain development. Many of them are considered here including: stem cell proliferation, fate determination, polarity, migration, process outgrowth, myelination and somatic hypertrophy. In many of these contexts, it is clear that PTEN phosphatase activity contributes to the observed effects of genetic deletion or depletion, however recent studies have also ascribed non-catalytic functions to PTEN in regulating cell function. We also explore the potential impact this alternative pool of PTEN may have on the developing brain. Together, these elements begin to form a clearer picture of how PTEN contributes to the emergence of brain structure and binds form and function in the nervous system.
    Full-text · Article · Apr 2014 · Frontiers in Molecular Neuroscience
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    • "Somatic hypertrophy among neurons has been one of the most consistent findings in cells with increased mTOR signaling (Figure 3). In animal models, somatic hypertrophy has been observed following deletion of TSC1 (Meikle et al., 2007; Zeng et al., 2008; Zhou et al., 2009; Tsai et al., 2012), TSC2 (Zeng et al., 2011; Tsai et al., 2014), and PTEN (Backman et al., 2001; Groszer et al., 2001; Kwon et al., 2001, 2003, 2006; Fraser et al., 2004; Ljungberg et al., 2009; Amiri et al., 2012; Pun et al., 2012). Hypertrophy has been detected in hippocampal granule cells (Backman et al., 2001; Kwon et al., 2001, 2003, 2006; Fraser et al., 2004; Amiri et al., 2012; Pun et al., 2012), cortical neurons (Fraser et al., 2004; Kwon et al., 2006; Meikle et al., 2007; Ljungberg et al., 2009; Zhou et al., 2009), and purkinje cells (Tsai et al., 2012; Thomanetz et al., 2013). "
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    ABSTRACT: The phosphatidylinositol-3-kinase/phosphatase and tensin homolog (PTEN)-mammalian target of rapamycin (mTOR) pathway regulates a variety of neuronal functions, including cell proliferation, survival, growth, and plasticity. Dysregulation of the pathway is implicated in the development of both genetic and acquired epilepsies. Indeed, several causal mutations have been identified in patients with epilepsy, the most prominent of these being mutations in PTEN and tuberous sclerosis complexes 1 and 2 (TSC1, TSC2). These genes act as negative regulators of mTOR signaling, and mutations lead to hyperactivation of the pathway. Animal models deleting PTEN, TSC1, and TSC2 consistently produce epilepsy phenotypes, demonstrating that increased mTOR signaling can provoke neuronal hyperexcitability. Given the broad range of changes induced by altered mTOR signaling, however, the mechanisms underlying seizure development in these animals remain uncertain. In transgenic mice, cell populations with hyperactive mTOR have many structural abnormalities that support recurrent circuit formation, including somatic and dendritic hypertrophy, aberrant basal dendrites, and enlargement of axon tracts. At the functional level, mTOR hyperactivation is commonly, but not always, associated with enhanced synaptic transmission and plasticity. Moreover, these populations of abnormal neurons can affect the larger network, inducing secondary changes that may explain paradoxical findings reported between cell and network functioning in different models or at different developmental time points. Here, we review the animal literature examining the link between mTOR hyperactivation and epileptogenesis, emphasizing the impact of enhanced mTOR signaling on neuronal form and function.
    Full-text · Article · Mar 2014 · Frontiers in Molecular Neuroscience
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