Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 4 de 4
Filter
Add more filters










Database
Language
Publication year range
1.
Nat Commun ; 15(1): 5887, 2024 Jul 13.
Article in English | MEDLINE | ID: mdl-39003305

ABSTRACT

Memory engrams are a subset of learning activated neurons critical for memory recall, consolidation, extinction and separation. While the transcriptional profile of engrams after learning suggests profound neural changes underlying plasticity and memory formation, little is known about how memory engrams are selected and allocated. As epigenetic factors suppress memory formation, we developed a CRISPR screening in the hippocampus to search for factors controlling engram formation. We identified histone lysine-specific demethylase 4a (Kdm4a) as a negative regulator for engram formation. Kdm4a is downregulated after neural activation and controls the volume of mossy fiber boutons. Mechanistically, Kdm4a anchors to the exonic region of Trpm7 gene loci, causing the stalling of nascent RNAs and allowing burst transcription of Trpm7 upon the dismissal of Kdm4a. Furthermore, the YTH domain containing protein 2 (Ythdc2) recruits Kdm4a to the Trpm7 gene and stabilizes nascent RNAs. Reducing the expression of Kdm4a in the hippocampus via genetic manipulation or artificial neural activation facilitated the ability of pattern separation in rodents. Our work indicates that Kdm4a is a negative regulator of engram formation and suggests a priming state to generate a separate memory.


Subject(s)
Hippocampus , Memory , TRPM Cation Channels , Animals , Hippocampus/metabolism , Mice , Memory/physiology , TRPM Cation Channels/metabolism , TRPM Cation Channels/genetics , Jumonji Domain-Containing Histone Demethylases/metabolism , Jumonji Domain-Containing Histone Demethylases/genetics , Humans , Down-Regulation/genetics , Neurons/metabolism , Male , Mice, Inbred C57BL , Rats , CRISPR-Cas Systems , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Neuronal Plasticity/genetics , HEK293 Cells , Histone Demethylases
2.
Angew Chem Int Ed Engl ; : e202410514, 2024 Jul 05.
Article in English | MEDLINE | ID: mdl-38966937

ABSTRACT

Organic scintillators are praised for their abundant element reserves, facile preparation procedures, and rich structures. Herein, a new family of highly efficient organic phosphonium halide salts with thermally activated delayed fluorescence (TADF) are designed by innovatively adopting quaternary phosphonium as the electron acceptor, while dimethylamine group and halide anions (I-) serve as the electron donor. The prepared butyl(2-[2-(dimethylamino)phenyl]phenyl)diphenylphosphonium iodide (C4-I) exhibits bright blue emission and an ultra-high photoluminescence quantum yield (PLQY) of 100%. Efficient charge transfer is realized through the unique n-π and anion-π stacking in solid-state C4-I. Photophysical studies of C4-I suggest that the incorporation of I accounts for high intersystem crossing rate (kISC) and reverse intersystem crossing rate (kRISC), suppressing the intrinsic prompt fluorescence and enabling near-pure TADF emission at room temperature. Benefitting from the large Stokes shift, high PLQY, efficient exciton utilization, and remarkable X-ray attenuation ability endowed by I, C4-I delivers an outstanding light yield of 80721 photons/MeV and a low limit of detection (LoD) of 22.79 nGy·s-1. This work would provide a rational design concept and open up an appealing road for developing efficient organic scintillators with tunable emission, strong X-ray attenuation ability, and excellent scintillator performance.

3.
Eur J Neurosci ; 55(6): 1424-1441, 2022 03.
Article in English | MEDLINE | ID: mdl-35181969

ABSTRACT

Adult newborn neurons are involved in memory encoding and extinction, but the neural mechanism is unclear. We found the adult newborn neurons at 4 weeks are recruited by learning and subjected to epigenetic regulations, consequently reducing their ability to be re-recruited later. After removal of the epigenetic blockage, Suv39h1 KO mice showed an increased recruiting number of aged newborn neurons and enhanced flexibility in learning tasks. Besides NRXN1, we found SHANK1, the synaptic scaffold protein, is one of the major targets of Suv39h1, regulating memory stability. Expression of Shank1 is transiently engaged to enhance synaptogenesis during learning and is strongly suppressed by Suv39h1 from 5 h after learning. Exogenously overexpression of Shank1 in dentate gyrus increased the density of mushroom spines and decreased the persistency of old memories. Our study indicated the activity-regulated epigenetic modification in newly matured newborn neurons in hippocampus insulates temporally distinct experiences and stabilizes old memories.


Subject(s)
Hippocampus , Neurons , Animals , Hippocampus/physiology , Learning , Methyltransferases , Mice , Mice, Inbred C57BL , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neurogenesis , Neurons/physiology , Repressor Proteins
4.
Neuron ; 110(7): 1156-1172.e9, 2022 04 06.
Article in English | MEDLINE | ID: mdl-35081333

ABSTRACT

ASD-associated genes are enriched for synaptic proteins and epigenetic regulators. How those chromatin modulators establish ASD traits have remained unknown. We find haploinsufficiency of Ash1l causally induces anxiety and autistic-like behavior, including repetitive behavior, and alters social behavior. Specific depletion of Ash1l in forebrain induces similar ASD-associated behavioral defects. While the learning ability remains intact, the discrimination ability of Ash1l mutant mice is reduced. Mechanistically, deletion of Ash1l in neurons induces excessive synapses due to the synapse pruning deficits, especially during the post-learning period. Dysregulation of synaptic genes is detected in Ash1l mutant brain. Specifically, Eph receptor A7 is downregulated in Ash1l+/- mice through accumulating EZH2-mediated H3K27me3 in its gene body. Importantly, increasing activation of EphA7 in Ash1l+/- mice by supplying its ligand, ephrin-A5, strongly promotes synapse pruning and rescues discrimination deficits. Our results suggest that Ash1l haploinsufficiency is a highly penetrant risk factor for ASD, resulting from synapse pruning deficits.


Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Animals , Autism Spectrum Disorder/genetics , Autism Spectrum Disorder/metabolism , Autistic Disorder/genetics , DNA-Binding Proteins/genetics , Disease Models, Animal , Haploinsufficiency , Histone-Lysine N-Methyltransferase/genetics , Mice , Mice, Knockout , Phenotype , Receptor, EphA1
SELECTION OF CITATIONS
SEARCH DETAIL
...