Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 188

Publication Record

Connections

Structures of the AMPA receptor in complex with its auxiliary subunit cornichon.
Nakagawa T
(2019) Science 366: 1259-1263
MeSH Terms: Animals, Brain, Cryoelectron Microscopy, Glutamic Acid, Ion Channel Gating, Protein Structure, Secondary, Protein Transport, Rats, Receptors, AMPA, Receptors, Glutamate, Synaptic Transmission
Show Abstract · Added March 3, 2020
In the brain, AMPA-type glutamate receptors (AMPARs) form complexes with their auxiliary subunits and mediate the majority of fast excitatory neurotransmission. Signals transduced by these complexes are critical for synaptic plasticity, learning, and memory. The two major categories of AMPAR auxiliary subunits are transmembrane AMPAR regulatory proteins (TARPs) and cornichon homologs (CNIHs); these subunits share little homology and play distinct roles in controlling ion channel gating and trafficking of AMPAR. Here, I report high-resolution cryo-electron microscopy structures of AMPAR in complex with CNIH3. Contrary to its predicted membrane topology, CNIH3 lacks an extracellular domain and instead contains four membrane-spanning helices. The protein-protein interaction interface that dictates channel modulation and the lipids surrounding the complex are revealed. These structures provide insights into the molecular mechanism for ion channel modulation and assembly of AMPAR/CNIH3 complexes.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
0 Communities
1 Members
0 Resources
11 MeSH Terms
Heterosynaptic GABA Receptor Function within Feedforward Microcircuits Gates Glutamatergic Transmission in the Nucleus Accumbens Core.
Manz KM, Baxley AG, Zurawski Z, Hamm HE, Grueter BA
(2019) J Neurosci 39: 9277-9293
MeSH Terms: Animals, GABA-B Receptor Agonists, Glutamic Acid, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nerve Net, Nucleus Accumbens, Organ Culture Techniques, Receptors, GABA-B, Synapses, Synaptic Transmission
Show Abstract · Added March 24, 2020
Complex circuit interactions within the nucleus accumbens (NAc) facilitate goal-directed behavior. Medium spiny neurons (MSNs) mediate NAc output by projecting to functionally divergent brain regions, a property conferred, in part, by the differential projection patterns of D1- and D2 dopamine receptor-expressing MSNs. Glutamatergic afferents to the NAc direct MSN output by recruiting feedforward inhibitory microcircuits comprised of parvalbumin (PV)-expressing interneurons (INs). Furthermore, the GABA heteroreceptor (GABAR), a G-coupled G-protein-coupled receptor, is expressed at glutamatergic synapses throughout the mesolimbic network, yet its physiological context and synaptic mechanism within the NAc remains unknown. Here, we explored GABAR function at glutamatergic synapses within PV-IN-embedded microcircuits in the NAc core of male mice. We found that GABAR is expressed presynaptically and recruits a noncanonical signaling mechanism to reduce glutamatergic synaptic efficacy at D1(+) and D1(-) (putative D2) MSN subtypes. Furthermore, PV-INs, a robust source of neuronal GABA in the NAc, heterosynaptically target GABAR to selectively modulate glutamatergic transmission onto D1(+) MSNs. These findings elucidate a new mechanism of feedforward inhibition and refine mechanisms by which GABA heteroreceptors modulate mesolimbic circuit function. Glutamatergic transmission in the nucleus accumbens (NAc) critically contributes to goal-directed behaviors. However, intrinsic microcircuit mechanisms governing the integration of these synapses remain largely unknown. Here, we show that parvalbumin-expressing interneurons within feedforward microcircuits heterosynaptically target GABA heteroreceptors (GABAR) on glutamate terminals. Activation of presynaptically-expressed GABAR decreases glutamatergic synaptic strength by engaging a non-canonical signaling pathway that interferes with vesicular exocytotic release machinery. These findings offer mechanistic insight into the role of GABA heteroreceptors within reward circuitry, elucidate a novel arm to feedforward inhibitory networks, and inform the growing use of GABAR-selective pharmacotherapy for various motivational disorders, including addiction, major depressive disorder, and autism (Cousins et al., 2002; Kahn et al., 2009; Jacobson et al., 2018; Stoppel et al., 2018; Pisansky et al., 2019).
Copyright © 2019 the authors.
0 Communities
1 Members
0 Resources
13 MeSH Terms
Disabling Gβγ-SNAP-25 interaction in gene-targeted mice results in enhancement of long-term potentiation at Schaffer collateral-CA1 synapses in the hippocampus.
Irfan M, Zurawski Z, Hamm HE, Bark C, Stanton PK
(2019) Neuroreport 30: 695-699
MeSH Terms: Animals, Excitatory Postsynaptic Potentials, Hippocampus, Long-Term Potentiation, Mice, Transgenic, Neuronal Plasticity, Synapses, Synaptic Transmission, Synaptosomal-Associated Protein 25, Temporal Lobe
Show Abstract · Added March 24, 2020
Three SNARE proteins, SNAP-25, syntaxin 1A, and VAMP2 or synaptobrevin 2, constitute the minimal functional machinery needed for the regulated secretion of neurotransmitters. Dynamic changes in the regulated release of neurotransmitters are associated with the induction of long-term plasticity at central synapses. In-vitro studies have validated the C-terminus of SNAP-25 as a target for inhibitory Gi/o-coupled G-protein coupled receptors at a number of synapses. The physiological consequences of the interaction between Gi/o proteins and SNAP-25 in the context of activity-dependent long-term synaptic plasticity are not well understood. Here, we report direct ex-vivo evidence of the involvement of the C-terminus of SNAP-25 in inducing long-term potentiation of synaptic strength at Schaffer collateral-CA1 synapses using a gene-targeted mouse model with truncated C-terminus (carboxyl terminus) of SNAP-25. It has been shown previously that truncation of the three extreme C-terminal residues in SNAP-25[INCREMENT]3 homozygote mice reduces its interaction with the inhibitory Gβγ subunits two-fold. In in-vitro hippocampal slices, we show that these SNAP-25[INCREMENT]3 mice express significantly larger magnitude of long-term potentiation at hippocampal Schaffer collateral-CA1 synapses.
0 Communities
1 Members
0 Resources
10 MeSH Terms
Disabling the Gβγ-SNARE interaction disrupts GPCR-mediated presynaptic inhibition, leading to physiological and behavioral phenotypes.
Zurawski Z, Thompson Gray AD, Brady LJ, Page B, Church E, Harris NA, Dohn MR, Yim YY, Hyde K, Mortlock DP, Jones CK, Winder DG, Alford S, Hamm HE
(2019) Sci Signal 12:
MeSH Terms: Animals, Calcium, Exocytosis, GTP-Binding Protein alpha Subunits, Gi-Go, GTP-Binding Protein beta Subunits, GTP-Binding Protein gamma Subunits, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Knockout, Neural Inhibition, Phenotype, Protein Binding, Receptors, G-Protein-Coupled, Synaptic Transmission, Synaptosomal-Associated Protein 25
Show Abstract · Added February 22, 2019
G protein-coupled receptors (GPCRs) that couple to G proteins modulate neurotransmission presynaptically by inhibiting exocytosis. Release of Gβγ subunits from activated G proteins decreases the activity of voltage-gated Ca channels (VGCCs), decreasing excitability. A less understood Gβγ-mediated mechanism downstream of Ca entry is the binding of Gβγ to SNARE complexes, which facilitate the fusion of vesicles with the cell plasma membrane in exocytosis. Here, we generated mice expressing a form of the SNARE protein SNAP25 with premature truncation of the C terminus and that were therefore partially deficient in this interaction. SNAP25Δ3 homozygote mice exhibited normal presynaptic inhibition by GABA receptors, which inhibit VGCCs, but defective presynaptic inhibition by receptors that work directly on the SNARE complex, such as 5-hydroxytryptamine (serotonin) 5-HT receptors and adrenergic α receptors. Simultaneously stimulating receptors that act through both mechanisms showed synergistic inhibitory effects. SNAP25Δ3 homozygote mice had various behavioral phenotypes, including increased stress-induced hyperthermia, defective spatial learning, impaired gait, and supraspinal nociception. These data suggest that the inhibition of exocytosis by G-coupled GPCRs through the Gβγ-SNARE interaction is a crucial component of numerous physiological and behavioral processes.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
1 Communities
3 Members
0 Resources
15 MeSH Terms
The expanding roles and mechanisms of G protein-mediated presynaptic inhibition.
Zurawski Z, Yim YY, Alford S, Hamm HE
(2019) J Biol Chem 294: 1661-1670
MeSH Terms: Action Potentials, Biochemistry, History, 20th Century, History, 21st Century, Humans, Periodicals as Topic, Presynaptic Terminals, Receptors, G-Protein-Coupled, Synaptic Transmission
Show Abstract · Added March 24, 2020
Throughout the past five decades, tremendous advancements have been made in our understanding of G protein signaling and presynaptic inhibition, many of which were published in the under the tenure of Herb Tabor as Editor-in-Chief. Here, we identify these critical advances, including the formulation of the ternary complex model of G protein-coupled receptor signaling and the discovery of Gβγ as a critical signaling component of the heterotrimeric G protein, along with the nature of presynaptic inhibition and its physiological role. We provide an overview for the discovery and physiological relevance of the two known Gβγ-mediated mechanisms for presynaptic inhibition: first, the action of Gβγ on voltage-gated calcium channels to inhibit calcium influx to the presynaptic active zone and, second, the direct binding of Gβγ to the SNARE complex to displace synaptotagmin downstream of calcium entry, which has been demonstrated to be important in neurons and secretory cells. These two mechanisms act in tandem with each other in a synergistic manner to provide more complete spatiotemporal control over neurotransmitter release.
© 2019 Zurawski et al.
0 Communities
1 Members
0 Resources
MeSH Terms
Synergistic Transcriptional Changes in AMPA and GABA Receptor Genes Support Compensatory Plasticity Following Unilateral Hearing Loss.
Balaram P, Hackett TA, Polley DB
(2019) Neuroscience 407: 108-119
MeSH Terms: Animals, Auditory Cortex, Auditory Pathways, Hearing Loss, Unilateral, Hyperacusis, Inferior Colliculi, Mice, Inbred C57BL, Mice, Transgenic, Neuronal Plasticity, Neurons, Receptors, AMPA, Receptors, GABA-A, Synaptic Transmission
Show Abstract · Added March 3, 2020
Debilitating perceptual disorders including tinnitus, hyperacusis, phantom limb pain and visual release hallucinations may reflect aberrant patterns of neural activity in central sensory pathways following a loss of peripheral sensory input. Here, we explore short- and long-term changes in gene expression that may contribute to hyperexcitability following a sudden, profound loss of auditory input from one ear. We used fluorescence in situ hybridization to quantify mRNA levels for genes encoding AMPA and GABA receptor subunits (Gria2 and Gabra1, respectively) in single neurons from the inferior colliculus (IC) and auditory cortex (ACtx). Thirty days after unilateral hearing loss, Gria2 levels were significantly increased while Gabra1 levels were significantly decreased. Transcriptional rebalancing was more pronounced in ACtx than IC and bore no obvious relationship to the degree of hearing loss. By contrast to the opposing, synergistic shifts in Gria2 and Gabra1 observed 30 days after hearing loss, we found that transcription levels for both genes were equivalently reduced after 5 days of hearing loss, producing no net change in the excitatory/inhibitory transcriptional balance. Opposing transcriptional shifts in AMPA and GABA receptor genes that emerge several weeks after a peripheral insult could promote both sensitization and disinhibition to support a homeostatic recovery of neural activity following auditory deprivation. Imprecise transcriptional changes could also drive the system toward perceptual hypersensitivity, degraded temporal processing and the irrepressible perception of non-existent environmental stimuli, a trio of perceptual impairments that often accompany chronic sensory deprivation.
Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.
0 Communities
1 Members
0 Resources
MeSH Terms
Metabotropic Glutamate Receptors in Alcohol Use Disorder: Physiology, Plasticity, and Promising Pharmacotherapies.
Joffe ME, Centanni SW, Jaramillo AA, Winder DG, Conn PJ
(2018) ACS Chem Neurosci 9: 2188-2204
MeSH Terms: Alcoholism, Animals, Humans, Limbic System, Neuronal Plasticity, Receptors, Metabotropic Glutamate, Synaptic Transmission
Show Abstract · Added March 26, 2019
Developing efficacious treatments for alcohol use disorder (AUD) has proven difficult. The insidious nature of the disease necessitates a deep understanding of its underlying biology as well as innovative approaches to ameliorate ethanol-related pathophysiology. Excessive ethanol seeking and relapse are generated by long-term changes to membrane properties, synaptic physiology, and plasticity throughout the limbic system and associated brain structures. Each of these factors can be modulated by metabotropic glutamate (mGlu) receptors, a diverse set of G protein-coupled receptors highly expressed throughout the central nervous system. Here, we discuss how different components of the mGlu receptor family modulate neurotransmission in the limbic system and other brain regions involved in AUD etiology. We then describe how these processes are dysregulated following ethanol exposure and speculate about how mGlu receptor modulation might restore such pathophysiological changes. To that end, we detail the current understanding of the behavioral pharmacology of mGlu receptor-directed drug-like molecules in animal models of AUD. Together, this review highlights the prominent position of the mGlu receptor system in the pathophysiology of AUD and provides encouragement that several classes of mGlu receptor modulators may be translated as viable treatment options.
0 Communities
1 Members
0 Resources
7 MeSH Terms
mGlu and mGlu modulate distinct excitatory inputs to the nucleus accumbens shell.
Turner BD, Rook JM, Lindsley CW, Conn PJ, Grueter BA
(2018) Neuropsychopharmacology 43: 2075-2082
MeSH Terms: Animals, Cocaine, Female, Mediodorsal Thalamic Nucleus, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Neuronal Plasticity, Neurons, Nucleus Accumbens, Optogenetics, Oxazoles, Prefrontal Cortex, Pyridines, Receptor, Metabotropic Glutamate 5, Receptors, Metabotropic Glutamate, Synapses, Synaptic Transmission
Show Abstract · Added March 3, 2020
Glutamatergic transmission in the nucleus accumbens shell (NAcSh) is a substrate for reward learning and motivation. Metabotropic glutamate (mGlu) receptors regulate NAcSh synaptic strength by inducing long-term depression (LTD). Inputs from prefrontal cortex (PFC) and medio-dorsal thalamus (MDT) drive opposing motivated behaviors yet mGlu receptor regulation of these synapses is unexplored. We examined Group I mGlu receptor regulation of PFC and MDT glutamatergic synapses onto specific populations of NAc medium spiny neurons (MSNs) using D1tdTom BAC transgenic mice and optogenetics. Synaptically evoked long-term depression (LTD) at MDT-NAcSh synapses required mGlu but not mGlu and was specific for D1(+) MSNs, whereas PFC LTD was expressed at both D1(+) and D1(-) MSNs and required mGlu but not mGlu. Two weeks after five daily non-contingent cocaine exposures (15 mg/kg), LTD was attenuated at MDT-D1(+) synapses but was rescued by the mGlu5-positive allosteric modulator (PAM) VU0409551. These results highlight unique plasticity mechanisms regulating specific NAcSh synapses.
0 Communities
1 Members
0 Resources
MeSH Terms
Introduction to the Thematic Minireview Series: Brain glycogen metabolism.
Carlson GM, Dienel GA, Colbran RJ
(2018) J Biol Chem 293: 7087-7088
MeSH Terms: Brain, Glycogen, Glycogenolysis, Glycolysis, Humans, Review Literature as Topic, Synaptic Transmission
Show Abstract · Added March 21, 2018
The synthesis of glycogen allows for efficient intracellular storage of glucose molecules in a soluble form that can be rapidly released to enter glycolysis in response to energy demand. Intensive studies of glucose and glycogen metabolism, predominantly in skeletal muscle and liver, have produced innumerable insights into the mechanisms of hormone action, resulting in the award of several Nobel Prizes over the last one hundred years. Glycogen is actually present in all cells and tissues, albeit at much lower levels than found in muscle or liver. However, metabolic and physiological roles of glycogen in other tissues are poorly understood. This series of Minireviews summarizes what is known about the enzymes involved in brain glycogen metabolism and studies that have linked glycogen metabolism to multiple brain functions involving metabolic communication between astrocytes and neurons. Recent studies unexpectedly linking some forms of epilepsy to mutations in two poorly understood proteins involved in glycogen metabolism are also reviewed.
© 2018 Carlson et al.
0 Communities
1 Members
0 Resources
7 MeSH Terms
Role of Striatal Direct Pathway 2-Arachidonoylglycerol Signaling in Sociability and Repetitive Behavior.
Shonesy BC, Parrish WP, Haddad HK, Stephenson JR, Báldi R, Bluett RJ, Marks CR, Centanni SW, Folkes OM, Spiess K, Augustin SM, Mackie K, Lovinger DM, Winder DG, Patel S, Colbran RJ
(2018) Biol Psychiatry 84: 304-315
MeSH Terms: Animals, Arachidonic Acids, Autism Spectrum Disorder, Corpus Striatum, Endocannabinoids, Glycerides, Mice, Mice, Knockout, Receptor, Adenosine A2A, Receptors, Dopamine D1, Signal Transduction, Social Behavior, Synaptic Transmission
Show Abstract · Added March 21, 2018
BACKGROUND - Endocannabinoid signaling plays an important role in regulating synaptic transmission in the striatum, a brain region implicated as a central node of dysfunction in autism spectrum disorder. Deficits in signaling mediated by the endocannabinoid 2-arachidonoylglycerol (2-AG) have been reported in mouse models of autism spectrum disorder, but a causal role for striatal 2-AG deficiency in phenotypes relevant to autism spectrum disorder has not been explored.
METHODS - Using conditional knockout mice, we examined the electrophysiological, biochemical, and behavioral effects of 2-AG deficiency by deleting its primary synthetic enzyme, diacylglycerol lipase α (DGLα), from dopamine D receptor-expressing or adenosine A2a receptor-expressing medium spiny neurons (MSNs) to determine the role of 2-AG signaling in striatal direct or indirect pathways, respectively. We then used viral-mediated deletion of DGLα to study the effects of 2-AG deficiency in the ventral and dorsal striatum.
RESULTS - Targeted deletion of DGLα from direct-pathway MSNs caused deficits in social interaction, excessive grooming, and decreased exploration of a novel environment. In contrast, deletion from indirect-pathway MSNs had no effect on any measure of behavior examined. Loss of 2-AG in direct-pathway MSNs also led to increased glutamatergic drive, which is consistent with a loss of retrograde feedback inhibition. Subregional DGLα deletion from the dorsal striatum produced deficits in social interaction, whereas deletion from the ventral striatum resulted in repetitive grooming.
CONCLUSIONS - These data suggest a role for 2-AG deficiency in social deficits and repetitive behavior, and they demonstrate a key role for 2-AG in regulating striatal direct-pathway MSNs.
Copyright © 2018 Society of Biological Psychiatry. All rights reserved.
0 Communities
2 Members
0 Resources
13 MeSH Terms