Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
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Neuropsychopharmacology · Dec 2014
Reduced phenotypic severity following adeno-associated virus-mediated Fmr1 gene delivery in fragile X mice.
Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by a trinucleotide repeat expansion in the FMR1 gene that codes for fragile X mental retardation protein (FMRP). To determine if FMRP expression in the central nervous system could reverse phenotypic deficits in the Fmr1 knockout (KO) mouse model of FXS, we used a single-stranded adeno-associated viral (AAV) vector with viral capsids from serotype 9 that contained a major isoform of FMRP. FMRP transgene expression was driven by the neuron-selective synapsin-1 promoter. ⋯ Cellular expression was selective for neurons and reached ∼ 50% of wild-type levels in the hippocampus and cortex at 56 days post injection. The pathologically elevated repetitive behavior and the deficit in social dominance behavior seen in phosphate-buffered saline-injected Fmr1 KO mice were reversed in AAV-FMRP-injected mice. These results provide the first proof of principle that gene therapy can correct specific behavioral abnormalities in the mouse model of FXS.
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Neuropsychopharmacology · Dec 2014
Upregulation of TREM2 ameliorates neuropathology and rescues spatial cognitive impairment in a transgenic mouse model of Alzheimer's disease.
Triggering receptor expressed on myeloid cells 2 (TREM2) gene is a recently identified susceptibility gene for Alzheimer's disease (AD), as its low-frequency variants increase the risk of this disease with an odds ratio similar to that of an APOE ɛ4 allele. To date, the expression and biologic functions of TREM2 under AD context remain largely unknown. Using APPswe/PS1dE9 mice, a transgenic model of AD, we showed that TREM2 was upregulated in microglia during disease progression. ⋯ More importantly, overexpression of TREM2 in the brain of APPswe/PS1dE9 mice markedly ameliorated AD-related neuropathology including Aβ deposition, neuroinflammation, and neuronal and synaptic losses, which was accompanied by an improvement in spatial cognitive functions. Taken together, our data suggest that the upregulation of TREM2 serves as a compensatory response to Aβ(1-42) and subsequently protects against AD progression by modulation of microglia functions. These findings provide insights into the role of TREM2 in AD pathogenesis, and highlight TREM2 as a potential therapeutic target for this disease.
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Neuropsychopharmacology · Dec 2014
Effect of GABRA2 genotype on development of incentive-motivation circuitry in a sample enriched for alcoholism risk.
Heightened reactivity of the incentive-motivation system has been proposed to underlie adolescent-typical risky behaviors, including problem alcohol involvement. However, even in adolescence considerable individual variation in these behaviors exists, which may have genetic underpinnings and be related to variations in risk for later alcohol use disorder (AUD). Variants in GABRA2 have been associated with adult alcohol dependence as well as phenotypic precursors, including impulsiveness and externalizing behaviors. ⋯ Furthermore, NAcc activation mediated an effect of genotype on alcohol problems (n = 104). This work demonstrates an impact of GABRA2 genotype on incentive-motivation neurocircuitry in adolescence, with implications for vulnerability to alcoholism. These findings represent an important step toward understanding the genetic and neural basis of individual differences in how risk for addiction unfolds across development.