Neuronal activity regulates the development and maturation of excitatory and inhibitory synapses in the mammalian brain. Several recent studies have identified signalling networks within neurons that control excitatory synapse development. However, less is known about the molecular mechanisms that regulate the activity-dependent development of GABA (γ-aminobutyric acid)-releasing inhibitory synapses. Here we report the identification of a transcription factor, Npas4, that plays a role in the development of inhibitory synapses by regulating the expression of activity-dependent genes, which in turn control the number of GABA-releasing synapses that form on excitatory neurons. These findings demonstrate that the activity-dependent gene program regulates inhibitory synapse development, and suggest a new role for this program in controlling the homeostatic balance between synaptic excitation and inhibition.

SUMMARY We report a novel mechanism of ribonucleoprotein (RNP) nucleocytoplasmic export by nuclear envelope budding. During development of Drosophila synapses, a fragment of the Wnt-1 receptor, DFrizzled2, is imported into postsynaptic nuclei where it forms prominent foci. We now show these foci to be composed of large RNP granules harboring synaptic protein transcripts. These RNPs exit the nucleus via a budding mechanism akin to nuclear egress of Herpes-type viruses, a process previously thought to be exclusive to these viruses. During this mechanism, RNP granules bud into the space between the inner and the outer nuclear membranes (the perinuclear space), in a manner dependent on Lamin C, a nuclear protein linked to muscular dystrophies. Like herpes virus nuclear egress, this process requires protein kinase C, which is known to disrupt the lamin through phosphorylation. We suggest that nuclear budding is an endogenous nuclear export pathway for large RNP granules.

We report the results of a genetic screen to identify molecules important for synapse formation and/or maintenance. siRNAs were used to decrease the expression of candidate genes in neurons, and synapse development was assessed. We surveyed 22 cadherin family members and demonstrated distinct roles for cadherin-11 and cadherin-13 in synapse development. Our screen also revealed roles for the class 4 Semaphorins Sema4B and Sema4D in the development of glutamatergic and/or GABAergic synapses. We found that Sema4D affects the formation of GABAergic, but not glutamatergic, synapses. Our screen also identified the activity-regulated small GTPase Rem2 as a regulator of synapse development. A known calcium channel modulator, Rem2 may function as part of a homeostatic mechanism that controls synapse number. These experiments establish the feasibility of RNAi screens to characterize the mechanisms that control mammalian neuronal development and to identify components of the genetic program that regulate synapse formation and/or maintenance.

Adrenergic signaling has important roles in synaptic plasticity and metaplasticity. However, the underlying mechanisms of these functions remain poorly understood. We investigated the role of octopamine, the invertebrate counterpart of adrenaline and noradrenaline, in synaptic and behavioral plasticity in Drosophila. We found that an increase in locomotor speed induced by food deprivation was accompanied by an activity- and octopamine-dependent extension of octopaminergic arbors and that the formation and maintenance of these arbors required electrical activity. Growth of octopaminergic arbors was controlled by a cAMP- and CREB-dependent positive-feedback mechanism that required Octpβ2R octopamine autoreceptors. Notably, this autoregulation was necessary for the locomotor response. In addition, octopamine neurons regulated the expansion of excitatory glutamatergic neuromuscular arbors through Octpβ2Rs on glutamatergic motor neurons. Our results provide a mechanism for global regulation of excitatory synapses, presumably to maintain synaptic and behavioral plasticity in a dynamic range.

Background The coronavirus disease (COVID-19) has posed an unprecedented challenge to governments worldwide. Effective government communication of COVID-19 information with the public is of crucial importance. Objective We investigate how the most-read state-owned newspaper in China, People’s Daily, used an online social networking site, Sina Weibo, to communicate about COVID-19 and whether this could engage the public. The objective of this study is to develop an integrated framework to examine the content, message style, and interactive features of COVID-19–related posts and determine their effects on public engagement in the largest social media network in China. Methods Content analysis was employed to scrutinize 608 COVID-19 posts, and coding was performed on three main dimensions: content, message style, and interactive features. The content dimension was coded into six subdimensions: action, new evidence, reassurance, disease prevention, health care services, and uncertainty, and the style dimension was coded into the subdimensions of narrative and nonnarrative. As for interactive features, they were coded into links to external sources, use of hashtags, use of questions to solicit feedback, and use of multimedia. Public engagement was measured in the form of the number of shares, comments, and likes on the People’s Daily’s Sina Weibo account from January 20, 2020, to March 11, 2020, to reveal the association between different levels of public engagement and communication strategies. A one-way analysis of variance followed by a post-hoc Tukey test and negative binomial regression analysis were employed to generate the results. Results We found that although the content frames of action, new evidence, and reassurance delivered in a nonnarrative style were predominant in COVID-19 communication by the government, posts related to new evidence and a nonnarrative style were strong negative predictors of the number of shares. In terms of generating a high number of shares, it was found that disease prevention posts delivered in a narrative style were able to achieve this purpose. Additionally, an interaction effect was found between content and style. The use of a narrative style in disease prevention posts had a significant positive effect on generating comments and likes by the Chinese public, while links to external sources fostered sharing. Conclusions These results have implications for governments, health organizations, medical professionals, the media, and researchers on their epidemic communication to engage the public. Selecting suitable communication strategies may foster active liking and sharing of posts on social media, which in turn, might raise the public’s awareness of COVID-19 and motivate them to take preventive measures. The sharing of COVID-19 posts is particularly important because this action can reach out to a large audience, potentially helping to contain the spread of the virus.

Neurite outgrowth is a crucial process in developing neurons for neural network formation. Understanding the regulatory mechanisms of neurite outgrowth is essential for developing strategies to stimulate neurite regeneration after nerve injury and in neurodegenerative disorders. FE65 is a brain-enriched adaptor that stimulates Rac1-mediated neurite elongation. However, the precise mechanism by which FE65 promotes the process remains elusive. Here, we show that ELMO1, a subunit of ELMO1-DOCK180 bipartite Rac1 guanine nucleotide exchange factor (GEF), interacts with the FE65 N-terminal region. Overexpression of FE65 and/or ELMO1 enhances, whereas knockdown of FE65 or ELMO1 inhibits, neurite outgrowth and Rac1 activation. The effect of FE65 alone or together with ELMO1 is attenuated by an FE65 double mutation that disrupts FE65-ELMO1 interaction. Notably, FE65 is found to activate ELMO1 by diminishing ELMO1 intramolecular autoinhibitory interaction and to promote the targeting of ELMO1 to the plasma membrane, where Rac1 is activated. We also show that FE65, ELMO1, and DOCK180 form a tripartite complex. Knockdown of DOCK180 reduces the stimulatory effect of FE65-ELMO1 on Rac1 activation and neurite outgrowth. Thus, we identify a novel mechanism by which FE65 stimulates Rac1-mediated neurite outgrowth by recruiting and activating ELMO1.

Adrenergic receptors and their ligands are important regulators of synaptic plasticity and metaplasticity, but the exact mechanisms underlying their action are still poorly understood. Octopamine, the invertebrate homolog of mammalian adrenaline or noradrenaline, plays important roles in modulating behavior and synaptic functions. We previously uncovered an octopaminergic positive feedback mechanism to regulate structural synaptic plasticity during development and in response to starvation. Under this mechanism, activation of Octß2R autoreceptors by octopamine at octopaminergic neurons initiated a cAMP-dependent cascade that stimulated the development of new synaptic boutons at the Drosophila larval neuromuscular junction (NMJ). However, the regulatory mechanisms that served to brake such positive feedback were not known. Here, we report the presence of an alternative octopamine autoreceptor, Octß1R, with antagonistic functions on synaptic growth. Mutations in octß1r result in the overgrowth of both glutamatergic and octopaminergic NMJs suggesting that Octß1R is a negative regulator of synaptic expansion. As Octß2R, Octß1R functioned in a cell autonomous manner at presynaptic motorneurons. However, unlike Octß2R, which activated a cAMP pathway, Octß1R likely inhibited cAMP production through inhibitory Goα. Despite its inhibitory role, Octß1R was required for acute changes in synaptic structure in response to octopamine and for starvation-induced increase in locomotor speed. These results demonstrate the dual action of octopamine on synaptic growth and behavioral plasticity, and highlight the important role of inhibitory influences for normal responses to physiological stimuli.

Polyglutamine (polyQ) diseases are a class of progressive neurodegenerative disorders characterized by the expression of both expanded RNA and misfolded polyQ protein. We previously reported that the direct interaction between expanded RNA and nucleolar protein nucleolin (NCL) impedes RNA () transcription, and eventually triggers nucleolar stress-induced apoptosis in polyQ diseases. Here, we report that a 21-amino acid peptide, named "beta-structured inhibitor for neurodegenerative diseases" (BIND), effectively suppresses toxicity induced by expanded RNA. When administered to a cell model, BIND potently inhibited cell death induced by expanded RNA with an IC value of ∼0.7 µM. We showed that the function of BIND is dependent on Glu2, Lys13, Gly14, Ile18, Glu19, and Phe20. BIND treatment restored the subcellular localization of nucleolar marker protein and the expression level of Through isothermal titration calorimetry analysis, we demonstrated that BIND suppresses nucleolar stress via a direct interaction with RNA in a length-dependent manner. The mean binding constants () of BIND to , , , and RNA are 17.28, 5.60, 4.83, and 0.66 µM, respectively. In vivo, BIND ameliorates retinal degeneration and climbing defects, and extends the lifespan of expressing expanded RNA. These effects suggested that BIND can suppress neurodegeneration in diverse polyQ disease models in vivo and in vitro without exerting observable cytotoxic effect. Our results collectively demonstrated that BIND is an effective inhibitor of expanded RNA-induced toxicity in polyQ diseases.