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AMPA Receptor Auxiliary Subunit GSG1L Suppresses Short-Term Facilitation in Corticothalamic Synapses and Determines Seizure Susceptibility.
Kamalova A, Futai K, Delpire E, Nakagawa T
(2020) Cell Rep 32: 107921
MeSH Terms: Animals, Cerebral Cortex, Claudins, Disease Susceptibility, Mice, Knockout, Neuronal Plasticity, Neurons, Protein Subunits, Seizures, Synapses, Thalamus
Show Abstract · Added July 28, 2020
The anterior thalamus (AT) is critical for memory formation, processing navigational information, and seizure initiation. However, the molecular mechanisms that regulate synaptic function of AT neurons remain largely unexplored. We report that AMPA receptor auxiliary subunit GSG1L controls short-term plasticity in AT synapses that receive inputs from the cortex, but not in those receiving inputs from other pathways. A canonical auxiliary subunit stargazin co-exists in these neurons but is functionally absent from corticothalamic synapses. In GSG1L knockout mice, AT neurons exhibit hyperexcitability and the animals have increased susceptibility to seizures, consistent with a negative regulatory role of GSG1L. We hypothesize that negative regulation of synaptic function by GSG1L plays a critical role in maintaining optimal excitation in the AT.
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
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11 MeSH Terms
TRESK and TREK-2 two-pore-domain potassium channel subunits form functional heterodimers in primary somatosensory neurons.
Lengyel M, Czirják G, Jacobson DA, Enyedi P
(2020) J Biol Chem 295: 12408-12425
MeSH Terms: Animals, HEK293 Cells, Humans, Ion Transport, Mice, Neurons, Potassium, Potassium Channels, Potassium Channels, Tandem Pore Domain, Protein Multimerization, Somatosensory Cortex, Xenopus laevis
Show Abstract · Added June 14, 2021
Two-pore-domain potassium channels (K) are the major determinants of the background potassium conductance. They play a crucial role in setting the resting membrane potential and regulating cellular excitability. These channels form homodimers; however, a few examples of heterodimerization have also been reported. The K channel subunits TRESK and TREK-2 provide the predominant background potassium current in the primary sensory neurons of the dorsal root and trigeminal ganglia. A recent study has shown that a TRESK mutation causes migraine because it leads to the formation of a dominant negative truncated TRESK fragment. Surprisingly, this fragment can also interact with TREK-2. In this study, we determined the biophysical and pharmacological properties of the TRESK/TREK-2 heterodimer using a covalently linked TRESK/TREK-2 construct to ensure the assembly of the different subunits. The tandem channel has an intermediate single-channel conductance compared with the TRESK and TREK-2 homodimers. Similar conductance values were recorded when TRESK and TREK-2 were coexpressed, demonstrating that the two subunits can spontaneously form functional heterodimers. The TRESK component confers calcineurin-dependent regulation to the heterodimer and gives rise to a pharmacological profile similar to the TRESK homodimer, whereas the presence of the TREK-2 subunit renders the channel sensitive to the selective TREK-2 activator T2A3. In trigeminal primary sensory neurons, we detected single-channel activity with biophysical and pharmacological properties similar to the TRESK/TREK-2 tandem, indicating that WT TRESK and TREK-2 subunits coassemble to form functional heterodimeric channels also in native cells.
© 2020 Lengyel et al.
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MeSH Terms
Osmotic Response of Dorsal Root Ganglion Neurons Expressing Wild-Type and Mutant KCC3 Transporters.
Flores B, Delpire E
(2020) Cell Physiol Biochem 54: 577-590
MeSH Terms: Animals, Axons, Cell Size, Corpus Callosum, Disease Models, Animal, Gain of Function Mutation, Ganglia, Spinal, Hereditary Sensory and Autonomic Neuropathies, Homeostasis, Humans, Membrane Transport Proteins, Mice, Mice, Knockout, Neurons, Osmotic Pressure, Symporters
Show Abstract · Added June 30, 2020
BACKGROUND/AIMS - Loss-of-Function (LOF) of the potassium chloride cotransporter 3 (KCC3) results in hereditary sensorimotor neuropathy with Agenesis of the Corpus Callosum (HSMN/ACC). Our KCC3 knockout mouse recapitulated axonal swelling and tissue vacuolization observed in autopsies of individuals with HSMN/ACC. We previously documented the first human case of a KCC3 gain-of-function (GOF) in which the patient also exhibited severe peripheral neuropathy. Furthermore, the GOF mouse model exhibited shrunken axons implicating the cotransporter in cell volume homeostasis. It is unclear how both KCC3 LOF and GOF lead to peripheral neuropathy. Thus, we sought to study differences in cell volume regulation of dorsal root ganglion neurons isolated from different mouse lines.
METHODS - Using wide-field microscopy, we measured calcein fluorescence intensity through pinhole measurements at the center of cells and compared cell swelling and cell volume regulation/recovery of wild-type, LOF, and GOF dorsal root ganglia neurons, as well as wild-type neurons treated with a KCC-specific inhibitor.
RESULTS - In contrast to control neurons that swell and volume regulate under a hypotonic challenge, neurons lacking KCC3 swell but fail to volume regulate. Similar data were observed in wild-type neurons treated with the KCC inhibitor. We also show that sensory neurons expressing a constitutively active KCC3 exhibited a blunted swelling phase compared to wild-type neurons, questioning the purely osmotic nature of the swelling phase.
CONCLUSION - These findings demonstrate the integral role of KCC3 in cell volume homeostasis and support the idea that cell volume homeostasis is critical to the health of peripheral nerves.
© Copyright by the Author(s). Published by Cell Physiol Biochem Press.
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16 MeSH Terms
A social encounter drives gene expression changes linked to neuronal function, brain development, and related disorders in mice expressing the serotonin transporter Ala56 variant.
O'Reilly KC, Anacker AMJ, Rogers TD, Forsberg CG, Wang J, Zhang B, Blakely RD, Veenstra-VanderWeele J
(2020) Neurosci Lett 730: 135027
MeSH Terms: Animals, Autism Spectrum Disorder, Brain, Disease Models, Animal, Gene Expression, Male, Mice, Neurons, Serotonin, Serotonin Plasma Membrane Transport Proteins, Social Behavior
Show Abstract · Added May 26, 2020
Multiple lines of evidence implicate the serotonin (5-HT) system in social function, including biomarker findings in autism spectrum disorder. In mice, knock-in of a rare Gly56Ala substitution in the serotonin transporter (SERT) causes elevated whole blood 5-HT levels, increased 5-HT clearance in the brain, and altered social and repetitive behavior. To further examine the molecular impact of this variant on social response, SERT Ala56 mutant mice and wildtype littermate controls were exposed to a social or non-social stimulus. We examined the differential activation of the prefrontal cortex, lateral amygdala, and medial amygdala, to social stimuli through RNA sequencing. Differentially expressed genes were enriched in axonal guidance signaling pathways, networks related to nervous system development and function, neurological and psychiatric disorders, and behavior. These identified pathways and networks may shed light on the molecular cascades underlying the impact of altered SERT function on social behavior.
Copyright © 2020 Elsevier B.V. All rights reserved.
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11 MeSH Terms
Uncovering cell biology in the third dimension.
Robertson GL, Romero-Morales AI, Lippmann ES, Gama V
(2020) Mol Biol Cell 31: 319-323
MeSH Terms: Brain, Cell Biology, Humans, Mitochondria, Neovascularization, Physiologic, Neurons, Organoids
Show Abstract · Added August 24, 2020
Developmental biology has long benefited from studies of classic model organisms. These model systems have provided the fundamental understanding of general principles of development, as well as insight into genes and signaling pathways that control unique aspects of cell fate specification and tissue morphogenesis. Because human brain development cannot be studied in vivo, scientists have relied on these model systems to study basic principles underlying the development of this complex organ as many of these genes and signaling pathways play conserved roles in human development. However, recent studies have shown species-specific signatures in neurodevelopment such as the transcriptome of outer-radial glia, suggesting use of a human-derived model remains imperative. Over the past decade, human stem cell-derived brain organoids have emerged as a biologically relevant model system to study normal human brain development and neurological diseases. Here, we provide a historical perspective of this emerging model system, discuss current systems and limitations, and propose that new mechanistic insight into cell biology can be revealed using these three-dimensional brain structures.
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7 MeSH Terms
Loss of non-canonical KCC2 functions promotes developmental apoptosis of cortical projection neurons.
Mavrovic M, Uvarov P, Delpire E, Vutskits L, Kaila K, Puskarjov M
(2020) EMBO Rep 21: e48880
MeSH Terms: Apoptosis, Chlorides, Epilepsy, Humans, Neurons, Symporters
Show Abstract · Added March 18, 2020
KCC2, encoded in humans by the SLC12A5 gene, is a multifunctional neuron-specific protein initially identified as the chloride (Cl ) extruder critical for hyperpolarizing GABA receptor currents. Independently of its canonical function as a K-Cl cotransporter, KCC2 regulates the actin cytoskeleton via molecular interactions mediated through its large intracellular C-terminal domain (CTD). Contrary to the common assumption that embryonic neocortical projection neurons express KCC2 at non-significant levels, here we show that loss of KCC2 enhances apoptosis of late-born upper-layer cortical projection neurons in the embryonic brain. In utero electroporation of plasmids encoding truncated, transport-dead KCC2 constructs retaining the CTD was as efficient as of that encoding full-length KCC2 in preventing elimination of migrating projection neurons upon conditional deletion of KCC2. This was in contrast to the effect of a full-length KCC2 construct bearing a CTD missense mutation (KCC2 ), which disrupts cytoskeletal interactions and has been found in patients with neurological and psychiatric disorders, notably seizures and epilepsy. Together, our findings indicate ion transport-independent, CTD-mediated regulation of developmental apoptosis by KCC2 in migrating cortical projection neurons.
© 2020 The Authors.
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6 MeSH Terms
Neuronal L-Type Calcium Channel Signaling to the Nucleus Requires a Novel CaMKIIα-Shank3 Interaction.
Perfitt TL, Wang X, Dickerson MT, Stephenson JR, Nakagawa T, Jacobson DA, Colbran RJ
(2020) J Neurosci 40: 2000-2014
MeSH Terms: Animals, Calcium Channels, L-Type, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Cell Nucleus, Gene Expression Regulation, Hippocampus, Mice, Mice, Inbred C57BL, Microfilament Proteins, Nerve Tissue Proteins, Neurons, Signal Transduction
Show Abstract · Added March 3, 2020
The activation of neuronal plasma membrane Ca channels stimulates many intracellular responses. Scaffolding proteins can preferentially couple specific Ca channels to distinct downstream outputs, such as increased gene expression, but the molecular mechanisms that underlie the exquisite specificity of these signaling pathways are incompletely understood. Here, we show that complexes containing CaMKII and Shank3, a postsynaptic scaffolding protein known to interact with L-type calcium channels (LTCCs), can be specifically coimmunoprecipitated from mouse forebrain extracts. Activated purified CaMKIIα also directly binds Shank3 between residues 829 and 1130. Mutation of Shank3 residues Arg-Arg-Lys to three alanines disrupts CaMKII binding and CaMKII association with Shank3 in heterologous cells. Our shRNA/rescue studies revealed that Shank3 binding to both CaMKII and LTCCs is important for increased phosphorylation of the nuclear CREB transcription factor and expression of c-Fos induced by depolarization of cultured hippocampal neurons. Thus, this novel CaMKII-Shank3 interaction is essential for the initiation of a specific long-range signal from LTCCs in the plasma membrane to the nucleus that is required for activity-dependent changes in neuronal gene expression during learning and memory. Precise neuronal expression of genes is essential for normal brain function. Proteins involved in signaling pathways that underlie activity-dependent gene expression, such as CaMKII, Shank3, and L-type calcium channels, are often mutated in multiple neuropsychiatric disorders. Shank3 and CaMKII were previously shown to bind L-type calcium channels, and we show here that Shank3 also binds to CaMKII. Our data show that each of these interactions is required for depolarization-induced phosphorylation of the CREB nuclear transcription factor, which stimulates the expression of c-Fos, a neuronal immediate early gene with key roles in synaptic plasticity, brain development, and behavior.
Copyright © 2020 the authors.
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12 MeSH Terms
Epidermal Growth Factor Signaling Promotes Sleep through a Combined Series and Parallel Neural Circuit.
Konietzka J, Fritz M, Spiri S, McWhirter R, Leha A, Palumbos S, Costa WS, Oranth A, Gottschalk A, Miller DM, Hajnal A, Bringmann H
(2020) Curr Biol 30: 1-16.e13
MeSH Terms: Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Epidermal Growth Factor, Neurons, Signal Transduction, Sleep
Show Abstract · Added March 3, 2020
Sleep requires sleep-active neurons that depolarize to inhibit wake circuits. Sleep-active neurons are under the control of homeostatic mechanisms that determine sleep need. However, little is known about the molecular and circuit mechanisms that translate sleep need into the depolarization of sleep-active neurons. During many stages and conditions in C. elegans, sleep requires a sleep-active neuron called RIS. Here, we defined the transcriptome of RIS and discovered that genes of the epidermal growth factor receptor (EGFR) signaling pathway are expressed in RIS. Because of cellular stress, EGFR directly activates RIS. Activation of EGFR signaling in the ALA neuron has previously been suggested to promote sleep independently of RIS. Unexpectedly, we found that ALA activation promotes RIS depolarization. Our results suggest that ALA is a drowsiness neuron with two separable functions: (1) it inhibits specific behaviors, such as feeding, independently of RIS, (2) and it activates RIS. Whereas ALA plays a strong role in surviving cellular stress, surprisingly, RIS does not. In summary, EGFR signaling can depolarize RIS by an indirect mechanism through activation of the ALA neuron that acts upstream of the sleep-active RIS neuron and through a direct mechanism using EGFR signaling in RIS. ALA-dependent drowsiness, rather than RIS-dependent sleep bouts, appears to be important for increasing survival after cellular stress, suggesting that different types of behavioral inhibition play different roles in restoring health. VIDEO ABSTRACT.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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7 MeSH Terms
GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions.
Gerhard DM, Pothula S, Liu RJ, Wu M, Li XY, Girgenti MJ, Taylor SR, Duman CH, Delpire E, Picciotto M, Wohleb ES, Duman RS
(2020) J Clin Invest 130: 1336-1349
MeSH Terms: Animals, Antidepressive Agents, Female, GABAergic Neurons, Gene Knockout Techniques, Glutamate Decarboxylase, Interneurons, Ketamine, Male, Mice, Mice, Transgenic, Parvalbumins, Receptors, N-Methyl-D-Aspartate, Sex Characteristics, Somatostatin
Show Abstract · Added March 18, 2020
A single subanesthetic dose of ketamine, an NMDA receptor (NMDAR) antagonist, produces rapid and sustained antidepressant actions in depressed patients, addressing a major unmet need for the treatment of mood disorders. Ketamine produces a rapid increase in extracellular glutamate and synaptic formation in the prefrontal cortex, but the initial cellular trigger that initiates this increase and ketamine's behavioral actions has not been identified. To address this question, we used a combination of viral shRNA and conditional mutation to produce cell-specific knockdown or deletion of a key NMDAR subunit, GluN2B, implicated in the actions of ketamine. The results demonstrated that the antidepressant actions of ketamine were blocked by GluN2B-NMDAR knockdown on GABA (Gad1) interneurons, as well as subtypes expressing somatostatin (Sst) or parvalbumin (Pvalb), but not glutamate principle neurons in the medial prefrontal cortex (mPFC). Further analysis of GABA subtypes showed that cell-specific knockdown or deletion of GluN2B in Sst interneurons blocked or occluded the antidepressant actions of ketamine and revealed sex-specific differences that are associated with excitatory postsynaptic currents on mPFC principle neurons. These findings demonstrate that GluN2B-NMDARs on GABA interneurons are the initial cellular trigger for the rapid antidepressant actions of ketamine and show sex-specific adaptive mechanisms to GluN2B modulation.
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15 MeSH Terms
Accumulators, Neurons, and Response Time.
Schall JD
(2019) Trends Neurosci 42: 848-860
MeSH Terms: Animals, Brain, Decision Making, Humans, Mind-Body Relations, Metaphysical, Models, Neurological, Models, Psychological, Neurons, Psychophysiology, Reaction Time
Show Abstract · Added March 18, 2020
The marriage of cognitive neurophysiology and mathematical psychology to understand decision-making has been exceptionally productive. This interdisciplinary area is based on the proposition that particular neurons or circuits instantiate the accumulation of evidence specified by mathematical models of sequential sampling and stochastic accumulation. This linking proposition has earned widespread endorsement. Here, a brief survey of the history of the proposition precedes a review of multiple conundrums and paradoxes concerning the accuracy, precision, and transparency of that linking proposition. Correctly establishing how abstract models of decision-making are instantiated by particular neural circuits would represent a remarkable accomplishment in mapping mind to brain. Failing would reveal challenging limits for cognitive neuroscience. This is such a vigorous area of research because so much is at stake.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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10 MeSH Terms