Striatal Transcriptome and Interactome Analysis of Shank3-overexpressing Mice Reveals the Connectivity between Shank3 and mTORC1 Signaling

Mania causes symptoms of hyperactivity, impulsivity, elevated mood, reduced anxiety and decreased need for sleep, which suggests that the dysfunction of the striatum, a critical component of the brain motor and reward system, can be causally associated with mania. However, detailed molecular pathophysiology underlying the striatal dysfunction in mania remains largely unknown. In this study, we aimed to identify the molecular pathways showing alterations in the striatum of SH3 and multiple ankyrin repeat domains 3 (Shank3)-overexpressing transgenic (TG) mice that display manic-like behaviors. The results of transcriptome analysis suggested that mammalian target of rapamycin complex 1 (mTORC1) signaling may be the primary molecular signature altered in the Shank3 TG striatum. Indeed, we found that striatal mTORC1 activity, as measured by mTOR S2448 phosphorylation, was significantly decreased in the Shank3 TG mice compared to wild-type (WT) mice. To elucidate the potential underlying mechanism, we re-analyzed previously reported protein interactomes, and detected a high connectivity between Shank3 and several upstream regulators of mTORC1, such as tuberous sclerosis 1 (TSC1), TSC2 and Ras homolog enriched in striatum (Rhes), via 94 common interactors that we denominated “Shank3-mTORC1 interactome”. We noticed that, among the 94 common interactors, 11 proteins were related to actin filaments, the level of which was increased in the dorsal striatum of Shank3 TG mice. Furthermore, we could co-immunoprecipitate Shank3, Rhes and Wiskott-Aldrich syndrome protein family verprolin-homologous protein 1 (WAVE1) proteins from the striatal lysate of Shank3 TG mice. By comparing with the gene sets of psychiatric disorders, we also observed that the 94 proteins of Shank3-mTORC1 interactome were significantly associated with bipolar disorder (BD). Altogether, our results suggest a protein interaction-mediated connectivity between Shank3 and certain upstream regulators of mTORC1 that might contribute to the abnormal striatal mTORC1 activity and to the manic-like behaviors of Shank3 TG mice

Integrative Brain Transcriptome Analysis Reveals Region-Specific and Broad Molecular Changes in Shank3-Overexpressing Mice

Variants of the SH3 and multiple ankyrin repeat domain 3 (SHANK3) gene, encoding excitatory postsynaptic core scaffolding proteins, are causally associated with numerous neurodevelopmental and neuropsychiatric disorders, including autism spectrum disorder (ASD), bipolar disorder, intellectual disability, and schizophrenia (SCZ). Although detailed synaptic changes of various Shank3 mutant mice have been well characterized, broader downstream molecular changes, including direct and indirect changes, remain largely unknown. To address this issue, we performed a transcriptome analysis of the medial prefrontal cortex (mPFC) of adult Shank3-overexpressing transgenic (TG) mice, using an RNA-sequencing approach. We also re-analyzed previously reported RNA-sequencing results of the striatum of adult Shank3 TG mice and of the prefrontal cortex of juvenile Shank3+/ΔC mice with a 50–70% reduction of Shank3 proteins. We found that several myelin-related genes were significantly downregulated specifically in the mPFC, but not in the striatum or hippocampus, of adult Shank3 TG mice by comparing the differentially expressed genes (DEGs) of the analyses side by side. Moreover, we also found nine common DEGs between the mPFC and striatum of Shank3 TG mice, among which we further characterized ASD- and SCZ-associated G protein-coupled receptor 85 (Gpr85), encoding an orphan Gpr interacting with PSD-95. Unlike the mPFC-specific decrease of myelin-related genes, we found that the mRNA levels of Gpr85 increased in multiple brain regions of adult Shank3 TG mice, whereas the mRNA levels of its family members, Gpr27 and Gpr173, decreased in the cortex and striatum. Intriguingly, in cultured neurons, the mRNA levels of Gpr27, Gpr85, and Gpr173 were modulated by the neuronal activity. Furthermore, exogenously expressed GPR85 was co-localized with PSD-95 and Shank3 in cultured neurons and negatively regulated the number of excitatory synapses, suggesting its potential role in homeostatic regulation of excitatory synapses in Shank3 TG neurons. Finally, we performed a gene set enrichment analysis of the RNA-sequencing results, which suggested that Shank3 could affect the directional expression pattern of numerous ribosome-related genes in a dosage-dependent manner. To sum up, these results reveal previously unidentified brain region-specific and broad molecular changes in Shank3-overexpressing mice, further elucidating the complexity of the molecular pathophysiology of SHANK3-associated brain disorders

Efficient Si Nanowire Array Transfer via Bi‐Layer Structure Formation Through Metal‐Assisted Chemical Etching

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106706/1/adfm201303180.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/106706/2/adfm201303180-sup-0001-S1.pd

Enhanced performance of lead sulfide quantum dot-sensitized solar cells by controlling the thickness of metal halide perovskite shells

The metal halide perovskite CH3NH3PbI3 (MAP) can be applied as the shell layer of lead sulfide quantum dots (PbS QDs) for improving solar power conversion efficiency. However, basic physics for this PbS core/MAP shell QD system is still unclear and needs to be clarified to further improve efficiency. Therefore, in this study, we investigate how MAP shell thickness affects device performance and dynamics of charge carriers for PbS QD-sensitized solar cells. Covering the PbS QDs with the MAP shell layers of an appropriate thickness around 0.34 nm greatly suppresses charge carrier recombination at surface defects along with improved carrier transport to neighboring oxide and polymer layers. Therefore, this MAP shell thickness provides the highest open-circuit voltage, short-circuit current density, and fill factor for solar cells. Overall power conversion efficiencies of these solar cells reached about 4.1%, which is about six-fold higher than that for solar cells without MAP (about 0.7%). Additionally, use of the MAP shell layers can prevent oxidation of PbS QDs and, therefore, makes a degradation of solar cell performance slower in air

Striatal transcriptome and interactome analysis of Shank3-overexpressing mice reveals the connectivity between Shank3 and mTORC1 signaling

Mania causes symptoms of hyperactivity, impulsivity, elevated mood, reduced anxiety and decreased need for sleep, which suggests that the dysfunction of the striatum, a critical component of the brain motor and reward system, can be causally associated with mania. However, detailed molecular pathophysiology underlying the striatal dysfunction in mania remains largely unknown. In this study, we aimed to identify the molecular pathways showing alterations in the striatum of SH3 and multiple ankyrin repeat domains 3 (Shank3)-overexpressing transgenic (TG) mice that display manic-like behaviors. The results of transcriptome analysis suggested that mammalian target of rapamycin complex 1 (mTORC1) signaling may be the primary molecular signature altered in the Shank3 TG striatum. Indeed, we found that striatal mTORC1 activity, as measured by mTOR S2448 phosphorylation, was significantly decreased in the Shank3 TG mice compared to wild-type (WT) mice. To elucidate the potential underlying mechanism, we re-analyzed previously reported protein interactomes, and detected a high connectivity between Shank3 and several upstream regulators of mTORC1, such as tuberous sclerosis 1 (TSC1), TSC2 and Ras homolog enriched in striatum (Rhes), via 94 common interactors that we denominated “Shank3-mTORC1 interactome”. We noticed that, among the 94 common interactors, 11 proteins were related to actin filaments, the level of which was increased in the dorsal striatum of Shank3 TG mice. Furthermore, we could co-immunoprecipitate Shank3, Rhes and Wiskott-Aldrich syndrome protein family verprolin-homologous protein 1 (WAVE1) proteins from the striatal lysate of Shank3 TG mice. By comparing with the gene sets of psychiatric disorders, we also observed that the 94 proteins of Shank3-mTORC1 interactome were significantly associated with bipolar disorder (BD). Altogether, our results suggest a protein interaction-mediated connectivity between Shank3 and certain upstream regulators of mTORC1 that might contribute to the abnormal striatal mTORC1 activity and to the manic-like behaviors of Shank3 TG mice. © 2017 Lee, Kim, Lee, Zhang, Kim, Kim, Kim, Kang and Han9

Comprehensive Physical Model of Dynamic Resistive Switching in an Oxide Memristor

Memristors have been proposed for a number of applications from nonvolatile memory to neuro­morphic systems. Unlike conventional devices based solely on electron transport, memristors operate on the principle of resistive switching (RS) based on redistribution of ions. To date, a number of experimental and modeling studies have been reported to probe the RS mechanism; however, a complete physical picture that can quantitatively describe the dynamic RS behavior is still missing. Here, we present a quantitative and accurate dynamic switching model that not only fully accounts for the rich RS behaviors in memristors in a unified framework but also provides critical insight for continued device design, optimization, and applications. The proposed model reveals the roles of electric field, temperature, oxygen vacancy concentration gradient, and different material and device parameters on RS and allows accurate predictions of diverse set/reset, analog switching, and complementary RS behaviors using only material-dependent device parameters

Spontaneous seizure and partial lethality of juvenile Shank3-overexpressing mice in C57BL/6 J background

Abstract The SH3 and multiple ankyrin repeat domains 3 (SHANK3) gene encodes core scaffolds in neuronal excitatory postsynapses. SHANK3 duplications have been identified in patients with hyperkinetic disorders and early-onset generalized tonic-clonic seizures. Consistently, Shank3 transgenic (TG) mice, which mildly overexpress Shank3 proteins exhibit hyperkinetic behavior and spontaneous seizures. However, the seizure phenotype of Shank3 TG mice has only been investigated in adults of the seizure-sensitive strain FVB/N. Therefore, it remains unknown if spontaneous seizures occur in Shank3 TG mice from the early postnatal stages onward, or even in seizure-resistant strains. Clinically, generalized tonic-clonic seizures are the critical risk factor for epilepsy-associated mortality. However, the potential association between Shank3 overexpression and mortality, at least in mice, has not been investigated in detail. In the present study, we backcrossed Shank3 TG mice in seizure-resistant C57BL/6 J strain and monitored their home-cage activities at 3 weeks of age. Of the 15 Shank3 TG mice monitored, two exhibited spontaneous tonic-clonic seizures, and one died immediately after the seizure event. Based on this observation, we determined the survival rate of the Shank3 TG mice from 3 to 12 weeks of age. We found that approximately 40–45% of the Shank3 TG mice, both males and females, died before reaching 12 weeks of age. Notably, 53% and 70% of the total deaths in male and female Shank3 TG mice, respectively, occurred in the juvenile stages. These results suggest spontaneous seizure and partial lethality of juvenile Shank3 TG mice in seizure-resistant background, further supporting the validity of this model

Transcriptome analysis of Shank3-overexpressing mice reveals unique molecular changes in the hypothalamus

Abstract Various mutations in the SH3 and multiple ankyrin repeat domains 3 (SHANK3) gene are associated with neurodevelopmental and neuropsychiatric disorders. Thus far, synaptic abnormalities in multiple brain regions, including the hippocampus, prefrontal cortex, striatum, and ventral tegmental area, have been investigated in several lines of Shank3 mutant mice. However, although some reports have shown loss and gain of body weight in Shank3 knock-out and overexpressing transgenic (TG) mice, respectively, the potential functions of Shank3 in the hypothalamus, a brain region critically involved in energy intake and expenditure, are unknown. Hence, we first characterized endogenous Shank3 mRNA and protein expression in the hypothalamus of adult wild-type mice. Thereafter, we performed transcriptome analysis (RNA-sequencing) in the hypothalamus of adult Shank3 TG mice which mildly overexpress Shank3 proteins. By comparing the 174 differentially expressed genes in the hypothalamus with those previously reported in the striatum and medial prefrontal cortex (mPFC) of Shank3 TG mice, we found that 159 were hypothalamus-specific while only 15 were also observed in either the striatum or mPFC. Furthermore, gene set enrichment analysis of the RNA-sequencing analysis revealed that ribosome-related genes were enriched especially in the up-regulated genes of Shank3 TG hypothalamus, which is in contrast to the results of the Shank3 TG striatum and mPFC analyses, where ribosome-related genes were enriched in the down-regulated genes. Beyond revealing endogenous Shank3 mRNA and protein expression in the hypothalamus, our results suggest unique molecular changes in the hypothalamus of Shank3 TG mice compared with those in the striatum and mPFC

Tuning Resistive Switching Characteristics of Tantalum Oxide Memristors through Si Doping

An oxide memristor device changes its internal state according to the history of the applied voltage and current. The principle of resistive switching (RS) is based on ion transport (<i>e.g.</i>, oxygen vacancy redistribution). To date, devices with bi-, triple-, or even quadruple-layered structures have been studied to achieve the desired switching behavior through device structure optimization. In contrast, the device performance can also be tuned through fundamental atomic-level design of the switching materials, which can directly affect the dynamic transport of ions and lead to optimized switching characteristics. Here, we show that doping tantalum oxide memristors with silicon atoms can facilitate oxygen vacancy formation and transport in the switching layer with adjustable ion hopping distance and drift velocity. The devices show larger dynamic ranges with easier access to the intermediate states while maintaining the extremely high cycling endurance (>10¹⁰ set and reset) and are well-suited for neuromorphic computing applications. As an example, we demonstrate different flavors of spike-timing-dependent plasticity in this memristor system. We further provide a characterization methodology to quantitatively estimate the effective hopping distance of the oxygen vacancies. The experimental results are confirmed through detailed <i>ab initio</i> calculations which reveal the roles of dopants and provide design methodology for further optimization of the RS behavior