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Odor mixtures of opposing valence unveil inter-glomerular crosstalk in the Drosophila antennal lobe.Nature Communications Mar 2019Evaluating odor blends in sensory processing is a crucial step for signal recognition and execution of behavioral decisions. Using behavioral assays and 2-photon...
Evaluating odor blends in sensory processing is a crucial step for signal recognition and execution of behavioral decisions. Using behavioral assays and 2-photon imaging, we have characterized the neural and behavioral correlates of mixture perception in the olfactory system of Drosophila. Mixtures of odors with opposing valences elicit strong inhibition in certain attractant-responsive input channels. This inhibition correlates with reduced behavioral attraction. We demonstrate that defined subsets of GABAergic interneurons provide the neuronal substrate of this computation at pre- and postsynaptic loci via GABA- and GABA receptors, respectively. Intriguingly, manipulation of single input channels by silencing and optogenetic activation unveils a glomerulus-specific crosstalk between the attractant- and repellent-responsive circuits. This inhibitory interaction biases the behavioral output. Such a form of selective lateral inhibition represents a crucial neuronal mechanism in the processing of conflicting sensory information.
Topics: Animals; Animals, Genetically Modified; Arthropod Antennae; Behavior, Animal; Drosophila melanogaster; Excitatory Postsynaptic Potentials; Female; GABAergic Neurons; Inhibitory Postsynaptic Potentials; Interneurons; Odorants; Olfactory Bulb; Olfactory Pathways; Olfactory Perception; Olfactory Receptor Neurons; Optogenetics; Receptors, Odorant
PubMed: 30867415
DOI: 10.1038/s41467-019-09069-1 -
Genes & Development May 2017Proper function of the neural network results from the precise connections between axons and dendrites of presynaptic and postsynaptic neurons, respectively. In the...
Proper function of the neural network results from the precise connections between axons and dendrites of presynaptic and postsynaptic neurons, respectively. In the olfactory system, the dendrites of projection neurons (PNs) stereotypically target one of ∼50 glomeruli in the antennal lobe (AL), the primary olfactory center in the brain, and form synapses with the axons of olfactory receptor neurons (ORNs). Here, we show that Eph and Ephrin, the well-known axon guidance molecules, instruct the dendrodendritic segregation during the discrete olfactory map formation. The Eph receptor tyrosine kinase is highly expressed and localized in the glomeruli related to reproductive behavior in the developing AL. In one of the pheromone-sensing glomeruli (DA1), the Eph cell-autonomously regulates its dendrites to reside in a single glomerulus by interacting with Ephrins expressed in adjacent PN dendrites. Our data demonstrate that the interaction between dendritic Eph and Ephrin is essential for the PN dendritic boundary formation in the DA1 olfactory circuit, potentially enabling strict segregation of odor detection between pheromones and the other odors.
Topics: Animals; Dendrites; Drosophila Proteins; Drosophila melanogaster; Gene Expression Profiling; Gene Expression Regulation, Developmental; Gene Knockdown Techniques; Membrane Proteins; Olfactory Receptor Neurons; RNA Interference; Receptor, EphA1
PubMed: 28637694
DOI: 10.1101/gad.297424.117 -
The Journal of Physiology Oct 2017The release probability of the odorant receptor neuron (ORN) is reportedly one of the highest in the brain and is predicted to impose a transient temporal filter on...
KEY POINTS
The release probability of the odorant receptor neuron (ORN) is reportedly one of the highest in the brain and is predicted to impose a transient temporal filter on postsynaptic cells. Mitral cells responded to high frequency ORN stimulation with sustained transmission, whereas external tufted cells responded transiently. The release probability of ORNs (0.7) was equivalent across mitral and external tufted cells and could be explained by a single pool of slowly recycling vesicles. The sustained response in mitral cells resulted from dendrodendritic amplification in mitral cells, which was blocked by NMDA and mGluR1 receptor antagonists, converting mitral cell responses to transient response profiles. Our results suggest that although the afferent ORN synapse shows strong synaptic depression, dendrodendritic circuitry in mitral cells produces robust amplification of brief afferent input, and thus the relative strength of axodendritic and dendrodendritic input determines the postsynaptic response profile.
ABSTRACT
Short-term synaptic plasticity is a critical regulator of neural circuits, and largely determines how information is temporally processed. In the olfactory bulb, afferent olfactory receptor neurons respond to increasing concentrations of odorants with barrages of action potentials, and their terminals have an extraordinarily high release probability. These features suggest that during naturalistic stimuli, afferent input to the olfactory bulb is subject to strong synaptic depression, presumably truncating the postsynaptic response to afferent stimuli. To examine this issue, we used single glomerular stimulation in mouse olfactory bulb slices to measure the synaptic dynamics of afferent-evoked input at physiological stimulus frequencies. In cell-attached recordings, mitral cells responded to high frequency stimulation with sustained responses, whereas external tufted cells responded transiently. Consistent with previous reports, olfactory nerve terminals onto both cell types had a high release probability (0.7), from a single pool of slowly recycling vesicles, indicating that the distinct responses of mitral and external tufted cells to high frequency stimulation did not originate presyaptically. Rather, distinct temporal response profiles in mitral cells and external tufted cells could be attributed to slow dendrodendritic responses in mitral cells, as blocking this slow current in mitral cells converted mitral cell responses to a transient response profile, typical of external tufted cells. Our results suggest that despite strong axodendritic synaptic depression, the balance of axodendritic and dendrodendritic circuitry in external tufted cells and mitral cells, respectively, tunes the postsynaptic responses to high frequency, naturalistic stimulation.
Topics: Animals; Female; Male; Mice; Mice, Inbred C57BL; Olfactory Bulb; Olfactory Receptor Neurons; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission; Synaptic Vesicles
PubMed: 28791713
DOI: 10.1113/JP274608 -
The EMBO Journal Jun 2014Postsynaptic density protein-95 (PSD-95) is a central element of the postsynaptic architecture of glutamatergic synapses. PSD-95 mediates postsynaptic localization of...
Postsynaptic density protein-95 (PSD-95) is a central element of the postsynaptic architecture of glutamatergic synapses. PSD-95 mediates postsynaptic localization of AMPA receptors and NMDA receptors and plays an important role in synaptic plasticity. PSD-95 is released from postsynaptic membranes in response to Ca(2+) influx via NMDA receptors. Here, we show that Ca(2+)/calmodulin (CaM) binds at the N-terminus of PSD-95. Our NMR structure reveals that both lobes of CaM collapse onto a helical structure of PSD-95 formed at its N-terminus (residues 1-16). This N-terminal capping of PSD-95 by CaM blocks palmitoylation of C3 and C5, which is required for postsynaptic PSD-95 targeting and the binding of CDKL5, a kinase important for synapse stability. CaM forms extensive hydrophobic contacts with Y12 of PSD-95. The PSD-95 mutant Y12E strongly impairs binding to CaM and Ca(2+)-induced release of PSD-95 from the postsynaptic membrane in dendritic spines. Our data indicate that CaM binding to PSD-95 serves to block palmitoylation of PSD-95, which in turn promotes Ca(2+)-induced dissociation of PSD-95 from the postsynaptic membrane.
Topics: Animals; Calmodulin; Cells, Cultured; Disks Large Homolog 4 Protein; Fluorescence; Hippocampus; Histological Techniques; Immunoblotting; Immunoprecipitation; Intracellular Signaling Peptides and Proteins; Magnetic Resonance Spectroscopy; Membrane Proteins; Models, Neurological; Neurons; Post-Synaptic Density; Protein Conformation; Rats
PubMed: 24705785
DOI: 10.1002/embj.201488126 -
Molecular Brain Mar 2014Zinc concentrates at excitatory synapses, both at the postsynaptic density and in a subset of glutamatergic boutons. Zinc can modulate synaptic plasticity, memory...
BACKGROUND
Zinc concentrates at excitatory synapses, both at the postsynaptic density and in a subset of glutamatergic boutons. Zinc can modulate synaptic plasticity, memory formation and nociception by regulating transmitter receptors and signal transduction pathways. Also, intracellular zinc accumulation is a hallmark of degenerating neurons in several neurological disorders. To date, no single zinc extrusion mechanism has been directly localized to synapses. Based on the presence of a canonical PDZ I motif in the Zinc Transporter-1 protein (ZnT1), we hypothesized that ZnT1 may be targeted to synaptic compartments for local control of cytosolic zinc. Using our previously developed protocol for the co-localization of reactive zinc and synaptic proteins, we further asked if ZnT1 expression correlates with presynaptic zinc content in individual synapses.
FINDINGS
Here we demonstrate that ZnT1 is a plasma membrane protein that is enriched in dendritic spines and in biochemically isolated synaptic membranes. Hippocampal CA1 synapses labelled by postembedding immunogold showed over a 5-fold increase in ZnT1 concentration at synaptic junctions compared with extrasynaptic membranes. Subsynaptic analysis revealed a peak ZnT1 density on the postsynaptic side of the synapse, < 10 nm away from the postsynaptic membrane. ZnT1 was found in the vast majority of excitatory synapses regardless of the presence of vesicular zinc in presynaptic boutons.
CONCLUSIONS
Our study has identified ZnT1 as a novel postsynaptic density protein, and it may help elucidate the role of zinc homeostasis in synaptic function and disease.
Topics: Animals; Cation Transport Proteins; Hippocampus; Mice; Mice, Inbred BALB C; Post-Synaptic Density; Synapses; Synaptic Vesicles
PubMed: 24602382
DOI: 10.1186/1756-6606-7-16 -
The Journal of Neuroscience : the... Nov 2001The localization and functions of kainate receptors (KARs) in the CNS are still poorly known. In the striatum, GluR6/7 and KA2 immunoreactivity is expressed...
The localization and functions of kainate receptors (KARs) in the CNS are still poorly known. In the striatum, GluR6/7 and KA2 immunoreactivity is expressed presynaptically in a subpopulation of glutamatergic terminals and postsynaptically in dendrites and spines. The goal of this study was to further characterize the subcellular and subsynaptic localization of kainate receptor subunits in the monkey striatum. Immunoperoxidase data reveal that the relative abundance of GluR6/7- and KA2-immunoreactive terminals is homogeneous throughout the striatum irrespective of the differential degree of striatal degeneration in Huntington's disease. Pre-embedding and post-embedding immunogold data indicate that >70% of the presynaptic or postsynaptic GluR6/7 and KA2 labeling is expressed intracellularly. In material stained with the post-embedding immunogold method, approximately one-third of plasma membrane-bound gold particles labeling in axon terminals and spines is associated with asymmetric synapses, thereby representing synaptic kainate receptor subunits. On the other hand, >60% of the plasma-membrane bound labeling is extrasynaptic. Both GluR6/7 and KA2 labeling in glutamatergic terminals often occurs in clusters of gold particles along the membrane of large vesicular organelles located at various distances from the presynaptic grid. Anterograde labeling from the primary motor cortex or the centromedian thalamic nucleus indicate that both corticostriatal and thalamostriatal terminals express presynaptic GluR6/7 and KA2 immunoreactivity in the postcommissural putamen. In conclusion, these data demonstrate that kainate receptors in the striatum display a pattern of subcellular distribution different from other ionotropic glutamate receptor subtypes, but consistent with their metabotropic-like functions recently shown in the hippocampus.
Topics: Animals; Antibody Specificity; Biotin; Blotting, Western; Cell Membrane; Corpus Striatum; Dextrans; Immunohistochemistry; Macaca mulatta; Male; Microscopy, Immunoelectron; Neurons; Organelles; Protein Subunits; Receptors, Kainic Acid; Saimiri; Synapses; GluK2 Kainate Receptor; GluK3 Kainate Receptor
PubMed: 11698586
DOI: 10.1523/JNEUROSCI.21-22-08746.2001 -
IUCrJ Jul 2017Rapid communication at the chemical synapse depends on the action of ion channels residing in the postsynaptic membrane. The channels open transiently upon the binding...
Rapid communication at the chemical synapse depends on the action of ion channels residing in the postsynaptic membrane. The channels open transiently upon the binding of a neurotransmitter released from the presynaptic nerve terminal, eliciting an electrical response. Membrane lipids also play a vital but poorly understood role in this process of synaptic transmission. The present study examines the lipid distribution around nicotinic acetylcholine (ACh) receptors in tubular vesicles made from postsynaptic membranes of the ray, taking advantage of the recent advances in cryo-EM. A segregated distribution of lipid molecules is found in the outer leaflet of the bilayer. Apparent cholesterol-rich patches are located in specific annular regions next to the transmembrane helices and also in a more extended 'microdomain' between the apposed δ subunits of neighbouring receptors. The particular lipid distribution can be interpreted straightforwardly in relation to the gating movements revealed by an earlier time-resolved cryo-EM study, in which the membranes were exposed briefly to ACh. The results suggest that in addition to stabilizing the protein, cholesterol may play a mechanical role by conferring local rigidity to the membrane so that there is productive coupling between the extracellular and membrane domains, leading to opening of the channel.
PubMed: 28875026
DOI: 10.1107/S2052252517005243 -
ELife Nov 2018Using FIB-SEM we report the entire synaptic connectome of glomerulus VA1v of the right antennal lobe in . Within the glomerulus we densely reconstructed all neurons,...
Using FIB-SEM we report the entire synaptic connectome of glomerulus VA1v of the right antennal lobe in . Within the glomerulus we densely reconstructed all neurons, including hitherto elusive local interneurons. The -positive, sexually dimorphic VA1v included >11,140 presynaptic sites with ~38,050 postsynaptic dendrites. These connected input olfactory receptor neurons (ORNs, 51 ipsilateral, 56 contralateral), output projection neurons (18 PNs), and local interneurons (56 of >150 previously reported LNs). ORNs are predominantly presynaptic and PNs predominantly postsynaptic; newly reported LN circuits are largely an equal mixture and confer extensive synaptic reciprocity, except the newly reported LN2V with input from ORNs and outputs mostly to monoglomerular PNs, however. PNs were more numerous than previously reported from genetic screens, suggesting that the latter failed to reach saturation. We report a matrix of 192 bodies each having 50 connections; these form 88% of the glomerulus' pre/postsynaptic sites.
Topics: Animals; Arthropod Antennae; Connectome; Drosophila melanogaster; Female; Nerve Net; Olfactory Receptor Neurons; Synapses
PubMed: 30382940
DOI: 10.7554/eLife.37550 -
The Journal of Neuroscience : the... Feb 2017Major signaling molecules initially characterized as key early developmental regulators are also essential for the plasticity of the nervous system. Previously, the...
Major signaling molecules initially characterized as key early developmental regulators are also essential for the plasticity of the nervous system. Previously, the Wingless (Wg)/Wnt pathway was shown to underlie the structural and electrophysiological changes during activity-dependent synaptic plasticity at the neuromuscular junction. A challenge remains to understand how this signal mediates the cellular changes underlying this plasticity. Here, we focus on the actin regulator Cortactin, a major organizer of protrusion, membrane mobility, and invasiveness, and define its new role in synaptic plasticity. We show that Cortactin is present presynaptically and postsynaptically at the NMJ and that it is a presynaptic regulator of rapid activity-dependent modifications in synaptic structure. Furthermore, animals lacking presynaptic Cortactin show a decrease in spontaneous release frequency, and presynaptic Cortactin is necessary for the rapid potentiation of spontaneous release frequency that takes place during activity-dependent plasticity. Most interestingly, Cortactin levels increase at stimulated synaptic terminals and this increase requires neuronal activity, transcription and depends on Wg/Wnt expression. Because it is not simply the presence of Cortactin in the presynaptic terminal but its increase that is necessary for the full range of activity-dependent plasticity, we conclude that it probably plays a direct and important role in the regulation of this process. In the nervous system, changes in activity that lead to modifications in synaptic structure and function are referred to as synaptic plasticity and are thought to be the basis of learning and memory. The secreted Wingless/Wnt molecule is a potent regulator of synaptic plasticity in both vertebrates and invertebrates. Understanding the molecular mechanisms that underlie these plastic changes is a major gap in our knowledge. Here, we identify a presynaptic effector molecule of the Wingless/Wnt signal, Cortactin. We show that this molecule is a potent regulator of modifications in synaptic structure and is necessary for the electrophysiological changes taking place during synaptic plasticity.
Topics: Animals; Animals, Genetically Modified; Cortactin; Drosophila; Drosophila Proteins; Excitatory Postsynaptic Potentials; Female; Gene Expression Regulation; Horseradish Peroxidase; Male; Mutation; Neuromuscular Junction; Neuronal Plasticity; Potassium Chloride; Presynaptic Terminals; RNA Interference; Signal Transduction; Synaptotagmin I; Transcription Factors; Tumor Suppressor Proteins; Wnt1 Protein
PubMed: 28123080
DOI: 10.1523/JNEUROSCI.1375-16.2017 -
Proceedings. Biological Sciences Nov 2022In the conventional model of serotonin neurotransmission, serotonin released by neurons in the midbrain raphe nuclei exerts its actions on forebrain neurons by... (Review)
Review
In the conventional model of serotonin neurotransmission, serotonin released by neurons in the midbrain raphe nuclei exerts its actions on forebrain neurons by interacting with a large family of post-synaptic receptors. The actions of serotonin are terminated by active transport of serotonin back into the releasing neuron, which is mediated by the serotonin reuptake transporter (SERT). Because SERT is expressed pre-synaptically and is widely thought to be the only serotonin transporter in the forebrain, the conventional model does not include serotonin transport into post-synaptic neurons. However, a large body of evidence accumulating since the 1970s has shown that serotonin, despite having a positive charge, can cross cell membranes through a diffusion-like process. Multiple low-affinity, high-capacity, sodium-independent transporters, widely expressed in the brain, allow the carrier-mediated diffusion of serotonin into forebrain neurons. The amount of serotonin crossing cell membranes through this mechanism under physiological conditions is considerable. Most prominent textbooks fail to include this alternative method of serotonin uptake in the brain, and even most neuroscientists are unaware of it. This failure has limited our understanding of a key regulator of serotonergic neurotransmission, impeded research on the potential intracellular actions of serotonin in post-synaptic neurons and glial cells, and may have impeded our understanding of the mechanism by which antidepressant medications reduce depressive symptoms.
Topics: Serotonin; Serotonin Plasma Membrane Transport Proteins; Neurons; Cell Membrane; Brain
PubMed: 36321487
DOI: 10.1098/rspb.2022.1565