10 research outputs found
Unruh effect of nonlocal field theories with a minimal length
The nonlocal field theory commonly requires a minimal length, and so it
appears to formulate the nonlocal theory in terms of the doubly special
relativity which makes the speed of light and the minimal length invariant
simultaneously. We set up a generic nonlocal model having the same set of
solutions as the local theory but allowing Lorentz violations due to the
minimal length. It is exactly corresponding to the model with the modified
dispersion relation in the doubly special relativity. For this model, we
calculate the modified Wightman function and the rate of response function by
using the Unruh-DeWitt detector method. It turns out that the Unruh effect
should be corrected by the minimal length related to the nonlocality in the
regime of the doubly special relativity. However, for the Lorentz-invariant
limit, it is shown that the Wightman function and the Unruh effect remain the
same as those of the local theory.Comment: 16 pages, version to appear in PL
Tanc2-mediated mTOR inhibition balances mTORC1/2 signaling in the developing mouse brain and human neurons
mTOR signaling, involving mTORC1 and mTORC2 complexes, critically regulates neural development and is implicated in various brain disorders. However, we do not fully understand all of the upstream signaling components that can regulate mTOR signaling, especially in neurons. Here, we show a direct, regulated inhibition of mTOR by Tanc2, an adaptor/scaffolding protein with strong neurodevelopmental and psychiatric implications. While Tanc2-null mice show embryonic lethality, Tanc2-haploinsufficient mice survive but display mTORC1/2 hyperactivity accompanying synaptic and behavioral deficits reversed by mTOR-inhibiting rapamycin. Tanc2 interacts with and inhibits mTOR, which is suppressed by mTOR-activating serum or ketamine, a fast-acting antidepressant. Tanc2 and Deptor, also known to inhibit mTORC1/2 minimally affecting neurodevelopment, distinctly inhibit mTOR in early- and late-stage neurons. Lastly, Tanc2 inhibits mTORC1/2 in human neural progenitor cells and neurons. In summary, our findings show that Tanc2 is a mTORC1/2 inhibitor affecting neurodevelopment.11Ysciescopu
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Early Correction of N-Methyl-D-Aspartate Receptor Function Improves Autistic-like Social Behaviors in Adult Shank2-/- Mice.
BACKGROUND: Autism spectrum disorder involves neurodevelopmental dysregulations that lead to visible symptoms at early stages of life. Many autism spectrum disorder-related mechanisms suggested by animal studies are supported by demonstrated improvement in autistic-like phenotypes in adult animals following experimental reversal of dysregulated mechanisms. However, whether such mechanisms also act at earlier stages to cause autistic-like phenotypes is unclear. METHODS: We used Shank2-/- mice carrying a mutation identified in human autism spectrum disorder (exons 6 and 7 deletion) and combined electrophysiological and behavioral analyses to see whether early pathophysiology at pup stages is different from late pathophysiology at juvenile and adult stages and whether correcting early pathophysiology can normalize late pathophysiology and abnormal behaviors in juvenile and adult mice. RESULTS: Early correction of a dysregulated mechanism in young mice prevents manifestation of autistic-like social behaviors in adult mice. Shank2-/- mice, known to display N-methyl-D-aspartate receptor (NMDAR) hypofunction and autistic-like behaviors at postweaning stages after postnatal day 21 (P21), show the opposite synaptic phenotype-NMDAR hyperfunction-at an earlier preweaning stage (∼P14). Moreover, this NMDAR hyperfunction at P14 rapidly shifts to NMDAR hypofunction after weaning (∼P24). Chronic suppression of the early NMDAR hyperfunction by the NMDAR antagonist memantine (P7-P21) prevents NMDAR hypofunction and autistic-like social behaviors from manifesting at later stages (∼P28 and P56). CONCLUSIONS: Early NMDAR hyperfunction leads to late NMDAR hypofunction and autistic-like social behaviors in Shank2-/- mice, and early correction of NMDAR dysfunction has the long-lasting effect of preventing autistic-like social behaviors from developing at later stages
Sexually dimorphic behavior, neuronal activity, and gene expression in Chd8-mutant mice
Autism spectrum disorders (ASDs) are four times more common in males than in females, but the underlying mechanisms are poorly understood. We characterized sexually dimorphic changes in mice carrying a heterozygous mutation in Chd8 (Chd8+/N2373K) that was first identified in human CHD8 (Asn2373LysfsX2), a strong ASD-risk gene that encodes a chromatin remodeler. Notably, although male mutant mice displayed a range of abnormal behaviors during pup, juvenile, and adult stages, including enhanced mother-seeking ultrasonic vocalization, enhanced attachment to reunited mothers, and isolation-induced self-grooming, their female counterparts do not. This behavioral divergence was associated with sexually dimorphic changes in neuronal activity, synaptic transmission, and transcriptomic profiles. Specifically, female mice displayed suppressed baseline neuronal excitation, enhanced inhibitory synaptic transmission and neuronal firing, and increased expression of genes associated with extracellular vesicles and the extracellular matrix. Our results suggest that a human CHD8 mutation leads to sexually dimorphic changes ranging from transcription to behavior in mice. © 2018, The Author(s
Early Correction of N-Methyl-D-Aspartate Receptor Function Improves Autistic-like Social Behaviors in Adult Shank2−/− Mice
BACKGROUND: Autism spectrum disorder involves neurodevelopmental dysregulations that lead to visible symptoms
at early stages of life. Many autism spectrum disorder–related mechanisms suggested by animal studies are
supported by demonstrated improvement in autistic-like phenotypes in adult animals following experimental
reversal of dysregulated mechanisms. However, whether such mechanisms also act at earlier stages to cause
autistic-like phenotypes is unclear.
METHODS: We used Shank22/2 mice carrying a mutation identified in human autism spectrum disorder (exons 6 and
7 deletion) and combined electrophysiological and behavioral analyses to see whether early pathophysiology at pup
stages is different from late pathophysiology at juvenile and adult stages and whether correcting early pathophysiology
can normalize late pathophysiology and abnormal behaviors in juvenile and adult mice.
RESULTS: Early correction of a dysregulated mechanism in young mice prevents manifestation of autistic-like social
behaviors in adult mice. Shank22/2 mice, known to display N-methyl-D-aspartate receptor (NMDAR) hypofunction
and autistic-like behaviors at postweaning stages after postnatal day 21 (P21), show the opposite synaptic
phenotype—NMDAR hyperfunction—at an earlier preweaning stage (wP14). Moreover, this NMDAR hyperfunction
at P14 rapidly shifts to NMDAR hypofunction after weaning (wP24). Chronic suppression of the early NMDAR
hyperfunction by the NMDAR antagonist memantine (P7–P21) prevents NMDAR hypofunction and autistic-like
social behaviors from manifesting at later stages (wP28 and P56).
CONCLUSIONS: Early NMDAR hyperfunction leads to late NMDAR hypofunction and autistic-like social behaviors in
Shank22/2 mice, and early correction of NMDAR dysfunction has the long-lasting effect of preventing autistic-like
social behaviors from developing at later stages. c. 2018 Society of Biological Psychiatry.11sciescopu