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Chen J.,Shanghai JiaoTong University | Alberts I.,City University of New York | Li X.,New York State Institute for Basic Research in Developmental Disabilities
International Journal of Developmental Neuroscience | Year: 2014

The IGF-I/PI3K/AKT/mTOR signaling pathway plays an important role in the regulation of cell growth, proliferation, differentiation, motility, survival, metabolism and protein synthesis. Insulin-like growth factor-I (IGF-I) is synthesized in the liver and fibroblasts, and its biological actions are mediated by the IGF-I receptor (IGF-IR). The binding of IGF-I to IGF-IR leads to the activation of phosphatidylinositol 3-kinase (PI3K). Activated PI3K stimulates the production of phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2] and phosphatidylinositol (3,4,5)-trisphosphate [PI(3,4,5)P3]. The PH domain of AKT (protein kinase B, PKB) (v-AKT murine thymoma viral oncogene homolog) binds to PI(4,5)P2 and PI(3,4,5)P3, followed by phosphorylation of the Thr308 and Ser473 regulatory sites. Tuberous sclerosis complex 1 (TSC1) and TSC2 are upstream regulators of mammalian target of rapamycin (mTOR) and downstream effectors of the PI3K/AKT signaling pathway. The activation of AKT suppresses the TSC1/TSC2 heterodimer, which is an upstream regulator of mTOR. Dysregulated IGF-I/PI3K/AKT/mTOR signaling has been shown to be associated with autism spectrum disorders (ASDs). In this review, we discuss the emerging evidence for a functional relationship between the IGF-I/PI3K/AKT/mTOR pathway and ASDs, as well as a possible role of this signaling pathway in the diagnosis and treatment of ASDs. © 2014 ISDN. Source


Wei H.,New York State Institute for Basic Research in Developmental Disabilities
PloS one | Year: 2012

Although the pathogenic mechanisms that underlie autism are not well understood, there is evidence showing that metabotropic and ionotropic glutamate receptors are hyper-stimulated and the GABAergic system is hypo-stimulated in autism. Memantine is an uncompetitive antagonist of NMDA receptors and is widely prescribed for treatment of Alzheimer's disease treatment. Recently, it has been shown to improve language function, social behavior, and self-stimulatory behaviors of some autistic subjects. However the mechanism by which memantine exerts its effect remains to be elucidated. In this study, we used cultured cerebellar granule cells (CGCs) from Fmr1 knockout (KO) mice, a mouse model for fragile X syndrome (FXS) and syndromic autism, to examine the effects of memantine on dendritic spine development and synapse formation. Our results show that the maturation of dendritic spines is delayed in Fmr1-KO CGCs. We also detected reduced excitatory synapse formation in Fmr1-KO CGCs. Memantine treatment of Fmr1-KO CGCs promoted cell adhesion properties. Memantine also stimulated the development of mushroom-shaped mature dendritic spines and restored dendritic spine to normal levels in Fmr1-KO CGCs. Furthermore, we demonstrated that memantine treatment promoted synapse formation and restored the excitatory synapses to a normal range in Fmr1-KO CGCs. These findings suggest that memantine may exert its therapeutic capacity through a stimulatory effect on dendritic spine maturation and excitatory synapse formation, as well as promoting adhesion of CGCs. Source


Qian W.,Nantong University | Liu F.,Nantong University | Liu F.,New York State Institute for Basic Research in Developmental Disabilities
Neuroscience Bulletin | Year: 2014

The neuronal microtubule-associated protein tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles in the brains of individuals with Alzheimer's disease and related neurodegenerative disorders. The adult human brain expresses six isoforms of tau generated by alternative splicing of exons 2, 3, and 10 of its pre-mRNA. Exon 10 encodes the second microtubule-binding repeat of tau. Its alternative splicing produces tau isoforms with either three or four microtubule-binding repeats, termed 3R-tau and 4Rtau. In the normal adult human brain, the level of 3R-tau is approximately equal to that of 4R-tau. Several silent and intronic mutations of the tau gene associated with FTDP-17T (frontotemporal dementia with Parkinsonism linked to chromosome 17 and specifically characterized by tau pathology) only disrupt exon 10 splicing, but do not influence the primary sequence of the tau protein. Thus, abnormal exon 10 splicing is sufficient to cause neurodegeneration and dementia. Here, we review the regulation of tau exon 10 splicing by cis-elements and trans-factors and summarize all the mutations associated with FTDP-17T and related tauopathies. The findings suggest that correction of exon 10 splicing may be a potential target for tau exon 10 splicing-related tauopathies. © 2014 Shanghai Institutes for Biological Sciences, CAS and Springer-Verlag. Source


Krinsky-McHale S.J.,New York State Institute for Basic Research in Developmental Disabilities | Silverman W.,Kennedy Krieger Institute
Developmental Disabilities Research Reviews | Year: 2013

Individuals with intellectual disability (ID) are now living longer with the majority of individuals reaching middle and even "old age." As a consequence of this extended longevity they are vulnerable to the same ageassociated health problems as elderly adults in the general population without ID. This includes dementia, a general term referring to a variety of diseases and conditions causing substantial loss of cognitive ability and functional declines; adults with Down syndrome are at especially high risk. A great deal of recent effort has focused on the very earliest detectable indicators of decline (and even prodromal stages of dementiacausing diseases). A condition called mild cognitive impairment (MCI) has been conceptually defined as a decline in functioning that is more severe than expected with typical brain aging but not severe enough to meet criteria for a diagnosis of dementia. Consensus criteria for both dementia and MCI have been developed for typically developing adults but are of limited applicability for adults with ID, given their pre-existing cognitive impairments. Early diagnosis will continue to be of growing importance, both to support symptomatic treatment and to prevent irreversible neuropathology when interventions are developed to slow or halt the progression of underlying disease. While the intellectual and developmental disabilities field has for some time recognized the need to develop bestpractices for the diagnosis of MCI and dementia, there remains a pressing need for empirically based assessment methods and classification criteria. © 2013 Wiley Periodicals, Inc. Source


Chen Y.,New York State Institute for Basic Research in Developmental Disabilities
Molecular neurobiology | Year: 2013

Alzheimer's disease (AD) can be divided into sporadic AD (SAD) and familial AD (FAD). Most AD cases are sporadic and result from multiple etiologic factors, including environmental, genetic, and metabolic factors, whereas FAD is caused by mutations in the presenilins or amyloid-β (Aβ) precursor protein (APP) genes. A commonly used animal model for AD is the 3xTg-AD transgenic mouse model, which harbors mutated presenilin 1, APP, and tau genes and thus represents a model of FAD. There is an unmet need in the field to characterize animal models representing different AD mechanisms, so that potential drugs for SAD can be evaluated preclinically in these animal models. A mouse model generated by intracerebroventricular (icv) administration of streptozocin (STZ), the icv-STZ mouse, shows many aspects of SAD. In this study, we compared the non-cognitive and cognitive behaviors as well as biochemical and immunohistochemical alterations between the icv-STZ mouse and the 3xTg-AD mouse. We found that both mouse models showed increased exploratory activity as well as impaired learning and spatial memory. Both models also demonstrated neuroinflammation, altered synaptic proteins and insulin/IGF-1 (insulin-like growth factor-1) signaling, and increased hyperphosphorylated tau in the brain. The most prominent brain abnormality in the icv-STZ mouse was neuroinflammation, and in the 3xTg-AD mouse it was elevation of hyperphosphorylated tau. These observations demonstrate the behavioral and neuropathological similarities and differences between the icv-STZ mouse and the 3xTg-AD mouse models and will help guide future studies using these two mouse models for the development of AD drugs. Source

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