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Long-term potentiation (LTP) of synaptic transmission is thought to be an important cellular mechanism underlying memory formation. A widely accepted model posits that LTP requires the cytoplasmic carboxyl tail (C-tail) of the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GluA1. To find the minimum necessary requirement of the GluA1 C-tail for LTP in mouse CA1 hippocampal pyramidal neurons, we used a single-cell molecular replacement strategy to replace all endogenous AMPA receptors with transfected subunits. In contrast to the prevailing model, we found no requirement of the GluA1 C-tail for LTP. In fact, replacement with the GluA2 subunit showed normal LTP, as did an artificially expressed kainate receptor not normally found at these synapses. The only conditions under which LTP was impaired were those with markedly decreased AMPA receptor surface expression, indicating a requirement for a reserve pool of receptors. These results demonstrate the synapse’s remarkable flexibility to potentiate with a variety of glutamate receptor subtypes, requiring a fundamental change in our thinking with regard to the core molecular events underlying synaptic plasticity. The minimal possible requirement for AMPA receptor trafficking during long-term potentiation is explored, revealing that no region of the receptor subunit is necessary, in contrast with previous work; the only requirement for LTP seems to be a large reserve of glutamate receptors. A rethink on LTP and memory Learning and memory formation are thought to involve long-term potentiation (LTP), a rapid and lasting increase in synaptic strength between two neurons. LTP has been well described at glutamatergic synapses in the hippocampus, a region of the brain that is required for the formation of new memories. This study suggests, however, that the prevailing model for LTP, focusing on a single neurotransmitter receptor protein — the AMPA receptor subunit GluA1 — needs to be reconsidered. Rather, it seems that no one particular glutamate receptor is critically important for the production of LTP: if there is a large enough pool available locally for a synapse, LTP will occur.

Rabies virus (RABV) invades the central nervous system and nearly always causes fatal disease in humans. How RABV interacts with host neuron membrane receptors to become internalized and cause rabid symptoms is not yet fully understood. Here, we identified a novel receptor of RABV, which RABV uses to infect neurons. We found that metabotropic glutamate receptor subtype 2 (mGluR2), a member of the G protein-coupled receptor family that is abundant in the central nervous system, directly interacts with RABV glycoprotein to mediate virus entry. RABV infection was drastically decreased after mGluR2 siRNA knock-down in cells. Antibodies to mGluR2 blocked RABV infection in cells in vitro. Moreover, mGluR2 ectodomain soluble protein neutralized the infectivity of RABV cell-adapted strains and a street strain in cells (in vitro) and in mice (in vivo). We further found that RABV and mGluR2 are internalized into cells and transported to early and late endosomes together. These results suggest that mGluR2 is a functional cellular entry receptor for RABV. Our findings may open a door to explore and understand the neuropathogenesis of rabies.

Asthma, accompanied by lung inflammation, bronchoconstriction and airway hyper-responsiveness, is a significant public health burden. Here we report that Mas-related G protein-coupled receptors (Mrgprs) are expressed in a subset of vagal sensory neurons innervating the airway and mediates cholinergic bronchoconstriction and airway hyper-responsiveness. These findings provide insights into the neural mechanisms underlying the pathogenesis of asthma.

Key Points Mechanotransduction, the conversion of a mechanical stimulus into a biological response, constitutes the basis of fundamental physiological processes, including the senses of touch and pain. In mammals, detection of mechanical forces by the somatosensory system is performed by primary afferent neurons that project long axons to the skin and to deeper body structures. Cutaneous mechanoreceptors are specialized to detect a wide range of mechanical stimuli including light brush of the skin, texture, vibration, touch and noxious pressure. The ability of these mechanoreceptors to detect mechanical cues relies on the presence of mechanosensitive channels on the sensory nerve endings that rapidly transform mechanical forces into electrical signals. Although it has been remarkably difficult to characterize mechanotranducer channels at the molecular level, recent studies have provided insights into the basic properties and molecular identities of mechanosensitive channels in mammalian sensory neurons. Such analyses suggest that mechanical stimulation activates cation channels that differ in their sensitivity to pressure and desensitization rates, and that may define different classes of mechanotransducer channels. Although the molecular characterization of mechanosensitive channels remains uncertain, recent studies suggest that transient receptor potential cation channel ankyrin1 (TRPA1) as well as piezo proteins contribute to the mechanotranducer apparatus in mammalian sensory neurons. Molecular identification of transducer channels will undoubtedly accelerate our understanding of mechanotransduction in mammals and of its impairments in disease and post-traumatic states. Mechanotransduction — the conversion of a mechanical stimulus into an electrical signal — underpins the senses of touch, pain and proprioception. Delmas and colleagues review emerging data on the characteristics of mechanosensitive currents in mammalian sensory neurons and discuss candidate proteins that might constitute the underlying mechanotransducer channels. The somatosensory system mediates fundamental physiological functions, including the senses of touch, pain and proprioception. This variety of functions is matched by a diverse array of mechanosensory neurons that respond to force in a specific fashion. Mechanotransduction begins at the sensory nerve endings, which rapidly transform mechanical forces into electrical signals. Progress has been made in establishing the functional properties of mechanoreceptors, but it has been remarkably difficult to characterize mechanotranducer channels at the molecular level. However, in the past few years, new functional assays have provided insights into the basic properties and molecular identity of mechanotransducer channels in mammalian sensory neurons. The recent identification of novel families of proteins as mechanosensing molecules will undoubtedly accelerate our understanding of mechanotransduction mechanisms in mammalian somatosensation.

GABA is a robust regulator of both developing and mature neural networks. It exerts many of its effects through GABA.sub.A receptors, which are heteropentamers assembled from a large array of subunits encoded by distinct genes. In mammals, there are 19 different GABA.sub.A subunit types, which are divided into the [alpha], [beta], [gamma], [delta], [epsilon], [qi], [theta] and [rho] subfamilies. The immense diversity of GABA.sub.A receptors is not fully understood. However, it is known that specific isoforms, with their distinct biophysical properties and expression profiles, tune responses to GABA. Although larval zebrafish are well-established as a model system for neural circuit analysis, little is known about GABA.sub.A receptors diversity and expression in this system. Here, using database analysis, we show that the zebrafish genome contains at least 23 subunits. All but the mammalian [theta] and [epsilon] subunits have at least one zebrafish ortholog, while five mammalian GABA.sub.A receptor subunits have two zebrafish orthologs. Zebrafish contain one subunit, [beta]4, which does not have a clear mammalian ortholog. Similar to mammalian GABA.sub.A receptors, the zebrafish [alpha] subfamily is the largest and most diverse of the subfamilies. In zebrafish there are eight [alpha] subunits, and RNA in situ hybridization across early zebrafish development revealed that they demonstrate distinct patterns of expression in the brain, spinal cord, and retina. Some subunits were very broadly distributed, whereas others were restricted to small populations of cells. Subunit-specific expression patterns in zebrafish resembled were those found in frogs and rodents, which suggests that the roles of different GABA.sub.A receptor isoforms are largely conserved among vertebrates. This study provides a platform to examine isoform specific roles of GABA.sub.A receptors within zebrafish neural circuits and it highlights the potential of this system to better understand the remarkable heterogeneity of GABA.sub.A receptors.

Key Points Synaptic NMDARs ( N -methyl- D -aspartate receptors) and AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors), two major classes of glutamate-gated ion channels, are localized to postsynaptic densities (PSDs) where they are structurally organized (and spatially restricted) in a large macromolecular signalling complex of scaffolding and adaptor proteins, which physically links the receptors to kinases, phosphatases and other downstream signalling proteins. NMDARs are synthesized and co-translationally assemble in the endoplasmic reticulum (ER) to form functional channels with differing physiological and pharmacological properties and distinct patterns of synaptic targeting. Nascent NMDARs are transported in vesicles with adaptor and scaffolding proteins by the kinesin motor KIF17 along microtubules in dendrites to synaptic sites. New research provides evidence that synaptic NMDAR number and subunit composition are not static, but change dynamically in a cell- and synapse-specific manner during development and in response to neuronal activity and sensory experience. Activity drives not only NMDAR synaptic targeting and incorporation, but also receptor retrieval, differential sorting of receptors into the endosomal–lysosomal pathway and lateral diffusion between synaptic and extrasynaptic sites. Homeostatic mechanisms limit NMDAR synaptic strength by regulating receptor number and phenotype at synaptic sites. Whereas activity blockade promotes alternative RNA splicing of the NR1 subunit and accelerates forward trafficking of NMDARs, chronic neuronal activity drives subunit-specific receptor internalization, intracellular sorting and protein degradation via the ubiquitin–proteasome system. Emerging evidence indicates that activity-dependent insertion and retrieval of NMDARs to and from synaptic sites mediates some forms of long-term potentiation (LTP) and long-term depression (LTD), cellular processes that are widely believed to be involved in learning and memory, as well as metaplasticity at central synapses. Dysregulation of NMDAR trafficking may have a role in the behavioural symptoms associated with neuropsychiatric disorders such as cocaine addiction, chronic alcohol abuse, schizophrenia and Alzheimer's disease. Lau and Zukin focus on the contribution of NMDARs to synaptic plasticity, reviewing the molecular mechanisms that underlie the regulation of subunit composition and receptor numbers in the postsynaptic density. They also discuss how these regulatory mechanisms are thought to contribute to addiction and neurological diseases. The number and subunit composition of synaptic N -methyl- D -aspartate receptors (NMDARs) are not static, but change in a cell- and synapse-specific manner during development and in response to neuronal activity and sensory experience. Neuronal activity drives not only NMDAR synaptic targeting and incorporation, but also receptor retrieval, differential sorting into the endosomal–lysosomal pathway and lateral diffusion between synaptic and extrasynaptic sites. An emerging concept is that activity-dependent, bidirectional regulation of NMDAR trafficking provides a dynamic and potentially powerful mechanism for the regulation of synaptic efficacy and remodelling, which, if dysregulated, can contribute to neuropsychiatric disorders such as cocaine addiction, Alzheimer's disease and schizophrenia.

Antidepressants increase adult hippocampal neurogenesis in animal models, but the underlying molecular mechanisms are unknown. In this study, we used human hippocampal progenitor cells to investigate the molecular pathways involved in the antidepressant-induced modulation of neurogenesis. Because our previous studies have shown that antidepressants regulate glucocorticoid receptor (GR) function, we specifically tested whether the GR may be involved in the effects of these drugs on neurogenesis. We found that treatment (for 3–10 days) with the antidepressant, sertraline, increased neuronal differentiation via a GR-dependent mechanism. Specifically, sertraline increased both immature, doublecortin (Dcx)-positive neuroblasts (+16%) and mature, microtubulin-associated protein-2 (MAP2)-positive neurons (+26%). This effect was abolished by the GR-antagonist, RU486. Interestingly, progenitor cell proliferation, as investigated by 5′-bromodeoxyuridine (BrdU) incorporation, was only increased when cells were co-treated with sertraline and the GR-agonist, dexamethasone, (+14%) an effect which was also abolished by RU486. Furthermore, the phosphodiesterase type 4 (PDE4)-inhibitor, rolipram, enhanced the effects of sertraline, whereas the protein kinase A (PKA)-inhibitor, H89, suppressed the effects of sertraline. Indeed, sertraline increased GR transactivation, modified GR phosphorylation and increased expression of the GR-regulated cyclin-dependent kinase-2 (CDK2) inhibitors, p27 Kip1 and p57 Kip2 . In conclusion, our data suggest that the antidepressant, sertraline, increases human hippocampal neurogenesis via a GR-dependent mechanism that requires PKA signaling, GR phosphorylation and activation of a specific set of genes. Our data point toward an important role for the GR in the antidepressant-induced modulation of neurogenesis in humans.

Background The R47H variant of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) confers greatly increased risk for Alzheimer’s disease (AD), reflective of a central role for myeloid cells in neurodegeneration. Understanding how this variant confers AD risk promises to provide important insights into how myeloid cells contribute to AD pathogenesis and progression. Methods In order to investigate this mechanism, CRISPR/Cas9 was used to generate a mouse model of AD harboring one copy of the single nucleotide polymorphism (SNP) encoding the R47H variant in murine Trem2 . TREM2 expression, myeloid cell responses to amyloid deposition, plaque burden, and neuritic dystrophy were assessed at 4 months of age. Results AD mice heterozygous for the Trem2 R47H allele exhibited reduced total Trem2 mRNA expression, reduced TREM2 expression around plaques, and reduced association of myeloid cells with plaques. These results were comparable to AD mice lacking one copy of Trem2 . AD mice heterozygous for the Trem2 R47H allele also showed reduced myeloid cell responses to amyloid deposition, including a reduction in proliferation and a reduction in CD45 expression around plaques. Expression of the Trem2 R47H variant also reduced dense core plaque number but increased plaque-associated neuritic dystrophy. Conclusions These data suggest that the AD-associated TREM2 R47H variant increases risk for AD by conferring a loss of TREM2 function and enhancing neuritic dystrophy around plaques.

BACKGROUND: The biological mechanisms that link the development of depression to metabolic disorders such as obesity and diabetes remain obscure. Dopamine- and plasticity-related signalling in mesolimbic reward circuitry is implicated in the pathophysiology and aetiology of depression. OBJECTIVE: To determine the impact of a palatable high-fat diet (HFD) on depressive-like behaviour and biochemical alterations in brain reward circuitry in order to understand the neural processes that may contribute to the development of depression in the context of diet-induced obesity (DIO). METHODS: Adult male C57Bl6 mice were placed on a HFD or ingredient-matched, low-fat diet for 12 weeks. At the end of the diet regimen, we assessed anxiety and depressive-like behaviour, corticosterone levels and biochemical changes in the midbrain and limbic brain regions. Nucleus accumbens (NAc), dorsolateral striatum (DLS) and ventral tegmental area dissections were subjected to SDS-PAGE and immunoblotting using antibodies against D1A receptor, D2 receptor, brain-derived neurotrophic factor (BDNF), phospho-DARPP-32(thr75), phospho-CREB and ΔFosB. RESULTS: HFD mice showed significant decreases in open arm time and centre time activity in elevated plus maze and open field tasks, respectively, and increased immobility (behavioural despair) in the forced swim test. Corticosterone levels following acute restraint stress were substantially elevated in HFD mice. HFD mice had significantly higher D2R, BDNF and ΔFosB, but reduced D1R, protein expression in the NAc. Notably, the expression of BDNF in both the NAc and DLS and phospho-CREB in the DLS was positively correlated with behavioural despair. CONCLUSIONS: Our results demonstrate that chronic consumption of high-fat food and obesity induce plasticity-related changes in reward circuitry that are associated with a depressive-like phenotype. As increases in striatal BDNF and CREB activity are well implicated in depressive behaviour and reward, we suggest these signalling molecules may mediate the effects of high-fat feeding and DIO to promote negative emotional states and depressive-like symptomology.