Haploinsufficiency of the SHANK3 gene is causally linked to autism spectrum disorder (ASD), and ASD-associated genes are also enriched for chromatin remodelers. Here we found that brief treatment ...with romidepsin, a highly potent class I histone deacetylase (HDAC) inhibitor, alleviated social deficits in Shank3-deficient mice, which persisted for ~3 weeks. HDAC2 transcription was upregulated in these mice, and knockdown of HDAC2 in prefrontal cortex also rescued their social deficits. Nuclear localization of β-catenin, a Shank3-binding protein that regulates cell adhesion and transcription, was increased in Shank3-deficient mice, which induced HDAC2 upregulation and social deficits. At the downstream molecular level, romidepsin treatment elevated the expression and histone acetylation of Grin2a and actin-regulatory genes and restored NMDA-receptor function and actin filaments in Shank3-deficient mice. Taken together, these findings highlight an epigenetic mechanism underlying social deficits linked to Shank3 deficiency, which may suggest potential therapeutic strategies for ASD patients bearing SHANK3 mutations.
Zheng et al. show that levels of histone methyltransferases EHMT1/2, and of the histone methylation H3K9me2, are elevated in prefrontal cortex of a familial Alzheimer's disease (FAD) mouse model and ...human postmortem tissue. Inhibition of EHMT1/2 rescues cognitive deficits by relieving H3K9me2-mediated repression of glutamate receptor transcription in FAD mice.
Abstract
Epigenetic dysregulation, which leads to the alteration of gene expression in the brain, is suggested as one of the key pathophysiological bases of ageing and neurodegeneration. Here we found that, in the late-stage familial Alzheimer's disease (FAD) mouse model, repressive histone H3 dimethylation at lysine 9 (H3K9me2) and euchromatic histone methyltransferases EHMT1 and EHMT2 were significantly elevated in the prefrontal cortex, a key cognitive region affected in Alzheimer's disease. Elevated levels of H3K9me2 were also detected in the prefrontal cortex region of post-mortem tissues from human patients with Alzheimer's disease. Concomitantly, H3K9me2 at glutamate receptors was increased in prefrontal cortex of aged FAD mice, which was linked to the diminished transcription, expression and function of AMPA and NMDA receptors. Treatment of FAD mice with specific EHMT1/2 inhibitors reversed histone hyper-methylation and led to the recovery of glutamate receptor expression and excitatory synaptic function in prefrontal cortex and hippocampus. Chromatin immunoprecipitation-sequencing (ChIP-seq) data indicated that FAD mice exhibited genome-wide increase of H3K9me2 enrichment at genes involved in neuronal signalling (including glutamate receptors), which was reversed by EHMT1/2 inhibition. Moreover, the impaired recognition memory, working memory, and spatial memory in aged FAD mice were rescued by the treatment with EHMT1/2 inhibitors. These results suggest that disrupted epigenetic regulation of glutamate receptor transcription underlies the synaptic and cognitive deficits in Alzheimer's disease, and targeting histone methylation enzymes may represent a novel therapeutic strategy for this prevalent neurodegenerative disorder.
Many of the genes disrupted in autism are identified as histone-modifying enzymes and chromatin remodelers, most prominently those that mediate histone methylation/demethylation. However, the role of ...histone methylation enzymes in the pathophysiology and treatment of autism remains unknown. To address this, we used mouse models of haploinsufficiency of the Shank3 gene (a highly penetrant monogenic autism risk factor), which exhibits prominent autism-like social deficits. We found that histone methyltransferases EHMT1 and EHMT2, as well as histone lysine 9 dimethylation (specifically catalyzed by EHMT1/2), were selectively increased in the prefrontal cortex (PFC) of Shank3-deficient mice and autistic human postmortem brains. Treatment with the EHMT1/2 inhibitor UNC0642 or knockdown of EHMT1/2 in PFC induced a robust rescue of autism-like social deficits in Shank3-deficient mice, and restored NMDAR-mediated synaptic function. Activity-regulated cytoskeleton-associated protein (Arc) was identified as one of the causal factors underlying the rescuing effects of UNC0642 on NMDAR function and social behaviors in Shank3-deficient mice. UNC0642 treatment also restored a large set of genes involved in neural signaling in PFC of Shank3-deficient mice. These results suggest that targeting histone methylation enzymes to adjust gene expression and ameliorate synaptic defects could be a potential therapeutic strategy for autism.
One of the core symptoms of autism spectrum disorder (ASD) is impaired social interaction. Currently, no pharmacotherapies exist for this symptom due to complex biological underpinnings and distinct ...genetic models which fail to represent the broad disease spectrum. One convincing hypothesis explaining social deficits in human ASD patients is amotivation, however it is unknown whether mouse models of ASD represent this condition. Here we used two highly trusted ASD mouse models (male Shank3‐deficient Shank3+/ΔC mice modeling the monogenic etiology of ASD, and inbred BTBR mice both male and female modeling the idiopathic and highly polygenic pathology for ASD) to evaluate the level of motivation to engage in a social interaction. In the behavioral paradigms utilized, a social stimulus was placed in the open arm of the elevated plus maze (EPM), or the light compartment of the light‐dark box (LDB). To engage in a social interaction, mice were thus required to endure innately aversive conditions (open areas, height, and/or light). In the modified EPM paradigm, both Shank3+/ΔC and BTBR mice demonstrated decreased open‐arm engagement with a social stimulus but not a novel object, suggesting reduced incentive to engage in a social interaction in these models. However, these deficits were not expressed under the less severe aversive pressures of the LDB. Collectively, we show that ASD mouse models exhibit diminished social interaction incentive, and provide a new investigation strategy facilitating the study of the neurobiological mechanisms underlying social reward and motivation deficits in neuropsychiatric disorders.
Rationale
Adverse psychosocial factors during early childhood or adolescence compromise neural structure and brain function, inducing susceptibility for many psychiatric disorders such as substance ...use disorder. Nevertheless, the mechanisms underlying early life stress-induced addiction vulnerability is still unclear, especially for opioids.
Objectives
To address this, we used a mouse heroin self-administration model to examine how chronic early social isolation (ESI) stress (5 weeks, beginning at weaning) affects the behavioral and neural responses to heroin during adulthood.
Results
We found that ESI stress did not alter the acquisition for sucrose or heroin self-administration, nor change the motivation for sucrose on a progressive ratio schedule. However, ESI stress induced an upward shift of heroin dose-response curve in female mice and increased motivation and seeking for heroin in both sexes. Furthermore, we examined the neuronal activity (measured by c-Fos expression) within the key brain regions of the mesocorticolimbic system, including the prelimbic cortex (PrL), infralimbic cortex (IL), nucleus accumbens (NAc) core and shell, caudate putamen, and ventral tegmental area (VTA). We found that ESI stress dampened c-Fos expression in the PrL, IL, and VTA after 14-day forced abstinence, while augmented the neuronal responses to heroin-predictive context and cue in the IL and NAc core. Moreover, ESI stress disrupted the association between c-Fos expression and attempted infusions during heroin-seeking test in the PrL.
Conclusions
These data indicate that ESI stress leads to increased seeking and motivation for heroin, and this may be associated with distinct changes in neuronal activities in different subregions of the mesocorticolimbic system.
Cullin 3 (Cul3) gene, which encodes a core component of the E3 ubiquitin ligase complex that mediates proteasomal degradation, has been identified as a true high-risk factor for autism. Here, by ...combining behavioral, electrophysiological, and proteomic approaches, we have examined how Cul3 deficiency contributes to the etiology of different aspects of autism. Heterozygous mice with forebrain Cul3 deletion displayed autism-like social interaction impairment and sensory-gating deficiency. Region-specific deletion of Cul3 leads to distinct phenotypes, with social deficits linked to the loss of Cul3 in prefrontal cortex (PFC), and stereotypic behaviors linked to the loss of Cul3 in striatum. Correlated with these behavioral alterations, Cul3 deficiency in forebrain or PFC induces NMDA receptor hypofunction, while Cul3 loss in striatum causes a cell type-specific alteration of neuronal excitability in striatal circuits. Large-scale profiling has identified sets of misregulated proteins resulting from Cul3 deficiency in different regions, including Smyd3, a histone methyltransferase involved in gene transcription. Inhibition or knockdown of Smyd3 in forebrain Cul3-deficient mice ameliorates social deficits and restores NMDAR function in PFC. These results have revealed for the first time a potential molecular mechanism underlying the manifestation of different autism-like behavioral deficits by Cul3 deletion in cortico-striatal circuits.
Phosphors emitting visible and near-infrared persistent luminescence have been explored extensively owing to their unusual properties and commercial interest in their applications such as ...glow-in-the-dark paints, optical information storage, and in vivo bioimaging. However, no persistent phosphor that features emissions in the ultraviolet C range (200-280 nm) has been known to exist so far. Here, we demonstrate a strategy for creating a new generation of persistent phosphor that exhibits strong ultraviolet C emission with an initial power density over 10 milliwatts per square meter and an afterglow of more than 2 h. Experimental characterizations coupled with first-principles calculations have revealed that structural defects associated with oxygen introduction-induced anion vacancies in fluoride elpasolite can function as electron traps, which capture and store a large number of electrons triggered by X-ray irradiation. Notably, we show that the ultraviolet C afterglow intensity of the yielded phosphor is sufficiently strong for sterilization. Our discovery of this ultraviolet C afterglow opens up new avenues for research on persistent phosphors, and it offers new perspectives on their applications in terms of sterilization, disinfection, drug release, cancer treatment, anti-counterfeiting, and beyond.
In this review, we focus on the following points: classifications of chlorophyll based on chemical structure, and its relationship with photophysical properties; biomedical-explored chemical ...modification of chlorophylls to control the molecular stacking; supramolecular structures, dynamic assembly or transformation in physiological condition; visual characterization of nanostructures and quantitative analysis of in situ assembly; biomedical utility based on assembly enhanced photoacoustic, fluorescence, PET, MRI and multimode imaging, as well as improved photodynamic, photothermal therapy.
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Chlorophylls are one of the most abundant organic pigments on the earth, which play an important role in the photosynthesis of plants, algae and bacteria. With the development of chromatography and chemical synthesis technology, many new chlorophylls from nature have been identified, and similar typical heterocyclic macrocyclic chlorophyll derivatives have also been designed and synthesized. Their chemical structures have significantly affected the absorption of light, energy transfer efficiency, excited-state lifetime, etc. Inspired by the chlorophylls interactions in chloroplasts for light-harvesting, we realized that intramolecular assembly and the resultant nanostructures played a more prominent role in their photophysical and photochemical properties, even in further biomedical applications, such as photodynamic and photothermal therapy, photocatalytic diagnosis, as well as optical, photoacoustic, magnetic resonance and nuclear medical imaging. In this review, we discuss the photo-properties of chlorophylls, overview the driving forces of assembly, and summarize biomedical-relevant advantages incorporated supramolecular nanostructures. In particular, the dynamic assembly under physiological condition provides unpredictable and interesting biological effects, such as aggregation/assembly induced drug retention in disease areas, optimized biodistribution and optimized the pharmacokinetics. The labeling on the assembly also provides a useful tool for us to observe the self-assembled nanostructures in vivo in a non-invasive way. Through the elaboration of different examples of chlorophylls, we hope to provide some inspiration for the biomedical application design of chlorophylls derivatives.
Insulin-like growth factor 1 (IGF1) influences synaptic function in addition to its role in brain development and aging. Although the expression levels of IGF1 and IGF1 receptor (IGF1R) peak during ...development and decline with age, the adult brain has abundant IGF1 or IGF1R expression. Studies reveal that IGF1 regulates the synaptic transmission in neurons from young animals. However, the action of IGF1 on neurons in the adult brain is still unclear. Here, we used prefrontal cortical (PFC) slices from adult mice (∼8 weeks old) to characterize the role of IGF1 on excitatory synaptic transmission in pyramidal neurons and the underlying molecular mechanisms. We first validated IGF1R expression in pyramidal neurons using translating ribosomal affinity purification assay. Then, using whole-cell patch-clamp recording, we found that IGF1 attenuated the amplitude of evoked excitatory postsynaptic current (EPSC) without affecting the frequency and amplitude of miniature EPSC. Furthermore, this decrease in excitatory neurotransmission was blocked by pharmacological inhibition of IGF1R or conditional knockdown of IGF1R in PFC pyramidal neurons. In addition, we determined that IGF1-induced decrease of EPSC amplitude was due to postsynaptic effect (internalization of a-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid receptors AMPAR) rather than presynaptic glutamate release. Finally, we found that inhibition of metabotropic glutamate receptor subtype-1 (mGluR1) abolished IGF1-induced attenuation of evoked EPSC amplitude and decrease of AMPAR expression at synaptic membrane, suggesting mGluR1-mediated endocytosis of AMPAR was involved. Taken together, these data provide the first evidence that IGF1 regulates excitatory synaptic transmission in adult PFC via the interaction between IGF1R-dependent signaling pathway and mGluR1-mediated AMPAR endocytosis.
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•IGF1 inhibits evoked excitatory synaptic transmission in adult PFC pyramidal neurons.•IGF1 reduces AMPAR surface expression in adult PFC.•IGF1 inhibits evoked EPSC via IGF1R/Erk1/2 signaling pathway.•mGluR1 is involved in IGF1-mediated reduction of evoked EPSC.•IGF1R in neurons is involved in IGF1-mediated inhibition of evoked EPSC.
Background
Clinical use of botulinum neurotoxins (BoNTs) in masticatory muscles is usually bilateral, but most studies on the functional consequences of BoNT treatment have used unilaterally treated ...animals.
Objectives
To test the hypothesis that bilateral BoNT treatment of the rabbit masseter hampers mastication and to assess its effects on bone density of the mandibular condyles.
Methods
Ten 5‐month‐old female rabbits received injections of BoNT into both masseter muscles and nine sham animals received saline. Body weight, incisor bite force during masseter tetany, and surface and fine‐wire electromyography (EMG) of the masseter and medial pterygoid muscles were assessed at regular intervals. Half the sample was terminated after 4 weeks and the remainder after 12 weeks. Muscles were weighed and mandibular condyles were scanned with microCT to analyse bone density.
Results
BoNT rabbits lost weight and required a soft‐food diet. Incisor occlusal force plummeted after BoNT injection and remained lower than the shams. The duration of masticatory cycles was increased in the BoNT rabbits for 5 weeks, with most of the increase due to the adductor burst. Masseteric EMG amplitude began to improve at Week 5, but remained low on the working side throughout the experiment. At the 12‐week endpoint, masseter muscles were smaller in the BoNT rabbits. Medial pterygoid muscles did not compensate. Condylar bone density was reduced.
Conclusion
Bilateral treatment of the rabbit masseter by BoNT severely affected chewing performance. Even after a 3‐month recovery period, deficits remained in bite force, muscle size and condylar bone density.
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