Common Mechanisms of Excitatory and Inhibitory Imbalance in Schizophrenia and Autism Spectrum Disorders

Current Molecular Medicine, Год журнала: 2015, Номер 15(2), С. 146 - 167

Опубликована: Март 18, 2015

Autism Spectrum Disorders (ASD) and Schizophrenia (SCZ) are cognitive disorders with complex genetic architectures but overlapping behavioral phenotypes, which suggests common pathway perturbations. Multiple lines of evidence implicate imbalances in excitatory inhibitory activity (E/I imbalance) as a shared pathophysiological mechanism. Thus, understanding the molecular underpinnings E/I imbalance may provi de essential insight into etiology these uncover novel targets for future drug discovery. Here, we review key genetic, physiological, neuropathological, functional, studies that suggest alterations to excitatory/inhibitory circuits keys ASD SCZ pathogenesis. Keywords: Autism, dendritic spine, imbalance, GABAergic interneuron, glutamatergic, mTOR, NMDAR, schizophrenia.

Язык: Английский

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Dendritic Spines: The Locus of Structural and Functional Plasticity

Physiological Reviews, Год журнала: 2014, Номер 94(1), С. 141 - 188

Опубликована: Янв. 1, 2014

The introduction of high-resolution time lapse imaging and molecular biological tools has changed dramatically the rate progress towards understanding complex structure-function relations in synapses central spiny neurons. Standing issues, including sequence structural processes leading to formation, morphological change, longevity dendritic spines, as well functions spines neurological/psychiatric diseases are being addressed a growing number recent studies. There still unsettled issues with respect spine formation plasticity: Are formed first, followed by synapse or emergence spine? What immediate long-lasting changes properties following exposure plasticity-producing stimulation? Is volume/shape indicative its function? These other this review, which highlights complexity pathways involved regulation structure function, contributes synaptic interactions health disease.

Язык: Английский

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Pharmacological Inhibition of mTORC1 Suppresses Anatomical, Cellular, and Behavioral Abnormalities in Neural-SpecificPtenKnock-Out Mice

Journal of Neuroscience, Год журнала: 2009, Номер 29(6), С. 1773 - 1783

Опубликована: Фев. 11, 2009

PTEN (phosphatase and tensin homolog deleted on chromosome ten) is a lipid phosphatase that counteracts the function of phosphatidylinositol-3 kinase (PI3K). Loss results in constitutive activation AKT downstream effectors correlates with many human cancers, as well various brain disorders, including macrocephaly, seizures, Lhermitte–Duclos disease, autism. We previously generated conditional Pten knock-out mouse line loss limited postmitotic neurons cortex hippocampus. -null developed neuronal hypertrophy polarity. The mutant mice exhibited macrocephaly behavioral abnormalities reminiscent certain features Here, we report rapamycin, specific inhibitor mammalian target rapamycin complex 1 (mTORC1), can prevent reverse hypertrophy, resulting amelioration subset PTEN-associated abnormal behaviors, providing evidence mTORC1 pathway critical for this phenotype.

Язык: Английский

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Molecular neurobiology of mTOR

Neuroscience, Год журнала: 2016, Номер 341, С. 112 - 153

Опубликована: Ноя. 23, 2016

Mammalian/mechanistic target of rapamycin (mTOR) is a serine-threonine kinase that controls several important aspects mammalian cell function. mTOR activity modulated by various intra- and extracellular factors; in turn, changes rates translation, transcription, protein degradation, signaling, metabolism, cytoskeleton dynamics. has been repeatedly shown to participate neuronal development the proper functioning mature neurons. Changes are often observed nervous system diseases, including genetic diseases (e.g., tuberous sclerosis complex, Pten-related syndromes, neurofibromatosis, Fragile X syndrome), epilepsy, brain tumors, neurodegenerative disorders (Alzheimer's disease, Parkinson's Huntington's disease). Neuroscientists only recently began deciphering molecular processes downstream function system. As result, we gaining knowledge about ways which aberrant lead diseases. In this review, provide comprehensive view system, with special focus on functions control autophagy) likely underlie contribution

Язык: Английский

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PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia

Brain, Год журнала: 2015, Номер 138(6), С. 1613 - 1628

Опубликована: Фев. 25, 2015

Malformations of cortical development containing dysplastic neuronal and glial elements, including hemimegalencephaly focal dysplasia, are common causes intractable paediatric epilepsy. In this study we performed multiplex targeted sequencing 10 genes in the PI3K/AKT pathway on brain tissue from 33 children who underwent surgical resection cortex for treatment Sequencing results were correlated with clinical, imaging, pathological immunohistological phenotypes. We identified mosaic activating mutations PIK3CA AKT3 cohort, cancer-associated hotspot megalencephaly, hemimegalencephaly, dysplasia type IIa. addition, a germline PTEN mutation was male but no peripheral manifestations hamartoma tumour syndrome. A spectrum imaging abnormalities found cohort. While patients more severe systemic likely to have detected mutations, routine histopathological studies did not predict status. elevated levels phosphorylated S6 ribosomal protein both neurons astrocytes all II specimens, regardless presence or absence mutations. contrast, expression patterns T308 S473 forms AKT vitro kinase activities discriminated between mutation-positive cortex, mutation-negative non-dysplasia epilepsy cortex. Our findings identify as an important cause epileptogenic malformations establish part single pathogenic spectrum. Dysplastic Using techniques histopathology, immunohistochemistry, deep resected affected children, Jansen et al. show that overlapping phenotypes associated upregulation PI3K/AKT/mTOR pathway.

Язык: Английский

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Role of mTOR in physiology and pathology of the nervous system

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Год журнала: 2007, Номер 1784(1), С. 116 - 132

Опубликована: Авг. 27, 2007

Язык: Английский

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BDNF induces transport of PSD-95 to dendrites through PI3K-AKT signaling after NMDA receptor activation

Nature Neuroscience, Год журнала: 2007, Номер 10(6), С. 702 - 711

Опубликована: Май 21, 2007

Язык: Английский

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mTOR signaling and its roles in normal and abnormal brain development

Frontiers in Molecular Neuroscience, Год журнала: 2014, Номер 7

Опубликована: Апрель 23, 2014

Target of rapamycin (TOR) was first identified in yeast as a target molecule rapamycin, an anti-fugal and immunosuppressant macrolide compound. In mammals, its orthologue is called mTOR (mammalian TOR). serine/threonine kinase that converges different extracellular stimuli, such nutrients growth factors, diverges into several biochemical reactions, including translation, autophagy, transcription, lipid synthesis among others. These reactions govern cell cause cells to attain anabolic state. Thus, the disruption signaling implicated wide array diseases cancer, diabetes, obesity. central nervous system (CNS), cascade activated by nutrients, neurotrophic neurotransmitters enhances protein (and possibly lipid) suppresses autophagy. processes contribute normal neuronal promoting their differentiation, neurite elongation branching, synaptic formation during development. Therefore, may degeneration abnormal neural While reduced associated with neurodegeneration, excess activation causes development neurons glia, leading brain malformation. this review, we introduce current state molecular knowledge complexes general. We then describe neurons, which leads translational enhancement, finally discuss link between normal/abnormal

Язык: Английский

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The ASD Living Biology: from cell proliferation to clinical phenotype

Molecular Psychiatry, Год журнала: 2018, Номер 24(1), С. 88 - 107

Опубликована: Июнь 19, 2018

Abstract Autism spectrum disorder (ASD) has captured the attention of scientists, clinicians and lay public because its uncertain origins striking unexplained clinical heterogeneity. Here we review genetic, genomic, cellular, postmortem, animal model, cell model evidence that shows ASD begins in womb. This leads to a new theory is multistage, progressive brain development, spanning nearly all prenatal life. can begin as early 1st 2nd trimester with disruption proliferation differentiation. It continues neural migration, laminar disorganization, altered neuron maturation neurite outgrowth, synaptogenesis reduced network functioning. Among most commonly reported high-confidence ( hcASD ) genes, 94% express during life affect these fetal processes neocortex, amygdala, hippocampus, striatum cerebellum. A majority genes are pleiotropic, proliferation/differentiation and/or synapse development. Proliferation subsequent stages also be disrupted by maternal immune activation trimester. Commonly implicated pathways, PI3K/AKT RAS/ERK, pleiotropic multiple from through functional In different individuals, variation how when pathways dysregulated, will lead different, even opposing effects, producing well later Thus, pathogenesis not set at one point time does reside process, but rather cascade pathogenic vast toddlers. Despite this knowledge biology womb, current research methods have provided individualized information: What early-age molecular cellular differences underlie each individual child? Without such knowledge, rapid advances biological-based diagnostic, prognostic, precision medicine treatments cannot occur. Missing, therefore, what call Living Biology. conceptual paradigm shift towards focus on abnormal underlying within living individual. The concept emphasizes specific need for foundational child’s development beginnings stages. Biology seeks linking genetic vitro molecular, measurements vivo post-natal presentation progression child. We first study, which confirms multistage nature provides fetal-stage explanation overgrowth. Within-child novel coin here advocates integration information generate group-level explanations, clinically useful prognoses, approaches truly beneficial infant toddler ASD.

Язык: Английский

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Dendritic spine formation and stabilization

Current Opinion in Neurobiology, Год журнала: 2009, Номер 19(2), С. 146 - 153

Опубликована: Апрель 1, 2009

Язык: Английский

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