scholarly journals Defective function of GABA-containing synaptic vesicles in mice lacking the AP-3B clathrin adaptor

2004 ◽  
Vol 167 (2) ◽  
pp. 293-302 ◽  
Author(s):  
Fubito Nakatsu ◽  
Motohiro Okada ◽  
Fumiaki Mori ◽  
Noriko Kumazawa ◽  
Hiroto Iwasa ◽  
...  
Keyword(s):  
Synaptic Vesicles ◽  
Neuronal Excitability ◽  
Critical Role ◽  
Physiological Role ◽  
Adaptor Protein ◽  
Epileptic Seizures ◽  
Gaba Release ◽  
Long Term Potentiation ◽  
Clathrin Adaptor ◽  
And Function

AP-3 is a member of the adaptor protein (AP) complex family that regulates the vesicular transport of cargo proteins in the secretory and endocytic pathways. There are two isoforms of AP-3: the ubiquitously expressed AP-3A and the neuron-specific AP-3B. Although the physiological role of AP-3A has recently been elucidated, that of AP-3B remains unsolved. To address this question, we generated mice lacking μ3B, a subunit of AP-3B. μ3B−/− mice suffered from spontaneous epileptic seizures. Morphological abnormalities were observed at synapses in these mice. Biochemical studies demonstrated the impairment of γ-aminobutyric acid (GABA) release because of, at least in part, the reduction of vesicular GABA transporter in μ3B−/− mice. This facilitated the induction of long-term potentiation in the hippocampus and the abnormal propagation of neuronal excitability via the temporoammonic pathway. Thus, AP-3B plays a critical role in the normal formation and function of a subset of synaptic vesicles. This work adds a new aspect to the pathogenesis of epilepsy.

Neuronal Excitability in Epileptogenic Zones Regulated by the Wnt/ Β-Catenin Pathway

2020 ◽  
Vol 19 (1) ◽  
pp. 2-11 ◽  
Author(s):  
Carmen Rubio ◽  
Elisa Taddei ◽  
Jorge Acosta ◽  
Verónica Custodio ◽  
Carlos Paz
Keyword(s):  
Neuronal Excitability ◽  
System Development ◽  
Wnt Signaling Pathway ◽  
Epileptic Seizures ◽  
Epileptic Activity ◽  
Nervous System Development ◽  
Hippocampal Neurogenesis ◽  
Mitochondrial Regulation ◽  
The Central Nervous System ◽  
And Function

: Epilepsy is a neurological disorder that involves abnormal and recurrent neuronal discharges, producing epileptic seizures. Recently, it has been proposed that the Wnt signaling pathway is essential for the central nervous system development and function because it modulates important processes such as hippocampal neurogenesis, synaptic clefting, and mitochondrial regulation. Wnt/β- catenin signaling regulates changes induced by epileptic seizures, including neuronal death. Several genetic studies associate Wnt/β-catenin signaling with neuronal excitability and epileptic activity. Mutations and chromosomal defects underlying syndromic or inherited epileptic seizures have been identified. However, genetic factors underlying the susceptibility of an individual to develop epileptic seizures have not been fully studied yet. In this review, we describe the genes involved in neuronal excitability in epileptogenic zones dependent on the Wnt/β-catenin pathway.

Pre- and Postsynaptic Activation of M-Channels By a Novel Opener Dampens Neuronal Firing and Transmitter Release

2007 ◽  
Vol 97 (1) ◽  
pp. 283-295 ◽  
Author(s):  
Asher Peretz ◽  
Anton Sheinin ◽  
Cuiyong Yue ◽  
Nurit Degani-Katzav ◽  
Gilad Gibor ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Critical Role ◽  
Hippocampal Slices ◽  
Gaba Release ◽  
Neuronal Firing ◽  
Dorsal Root Ganglion Neurons ◽  
Postsynaptic Currents ◽  
M Channels ◽  
Ganglion Neurons

The M-type K+ current (M-current), encoded by Kv7.2/3 (KCNQ2/3) K+ channels, plays a critical role in regulating neuronal excitability because it counteracts subthreshold depolarizations. Here we have characterized the functions of pre- and postsynaptic M-channels using a novel Kv7.2/3 channel opener, NH6, which we synthesized as a new derivative of N-phenylanthranilic acid. NH6 exhibits a good selectivity as it does not affect Kv7.1 and IKS K+ currents as well as NR1/NR2B, AMPA, and GABAA receptor-mediated currents. Superfusion of NH6 increased recombinant Kv7.2/3 current amplitude (EC50 = 18 μM) by causing a hyperpolarizing shift of the voltage activation curve and by markedly slowing the deactivation kinetics. Activation of native M-currents by NH6 robustly reduced the number of evoked and spontaneous action potentials in cultured cortical, hippocampal and dorsal root ganglion neurons. In hippocampal slices, NH6 decreased somatically evoked spike afterdepolarization of CA1 pyramidal neurons and induced regular firing in bursting neurons. Activation of M-channels by NH6, potently reduced the frequency of spontaneous excitatory and inhibitory postsynaptic currents. Activation of M-channels also decreased the frequency of miniature excitatory (mEPSC) and inhibitory (mIPSC) postsynaptic currents without affecting their amplitude and waveform, thus suggesting that M-channels presynaptically inhibit glutamate and GABA release. Our results suggest a role of presynaptic M-channels in the release of glutamate and GABA. They also indicate that M-channels act pre- and postsynaptically to dampen neuronal excitability.

LPA4 regulates blood and lymphatic vessel formation during mouse embryogenesis

Blood ◽  
2010 ◽  
Vol 116 (23) ◽  
pp. 5060-5070 ◽  
Author(s):  
Hayakazu Sumida ◽  
Kyoko Noguchi ◽  
Yasuyuki Kihara ◽  
Manabu Abe ◽  
Keisuke Yanagida ◽  
...  
Keyword(s):  
Critical Role ◽  
Lymphatic Vessels ◽  
Physiological Role ◽  
Lipid Mediator ◽  
Mural Cell ◽  
Mouse Embryogenesis ◽  
Mural Cells ◽  
Adult Mice ◽  
Cell Coverage ◽  
And Function

Abstract Lysophosphatidic acid (LPA) is a potent lipid mediator with a wide variety of biological actions mediated through G protein-coupled receptors (LPA1-6). LPA4 has been identified as a G13 protein-coupled receptor, but its physiological role is unknown. Here we show that a subset of LPA4-deficient embryos did not survive gestation and displayed hemorrhages and/or edema in many organs at multiple embryonic stages. The blood vessels of bleeding LPA4-deficient embryos were often dilated. The recruitment of mural cells, namely smooth muscle cells and pericytes, was impaired. Consistently, Matrigel plug assays showed decreased mural cell coverage of endothelial cells in the neovessels of LPA4-deficient adult mice. In situ hybridization detected Lpa4 mRNA in the endothelium of some vasculatures. Similarly, the lymphatic vessels of edematous embryos were dilated. These results suggest that LPA4 regulates establishment of the structure and function of blood and lymphatic vessels during mouse embryogenesis. Considering the critical role of autotaxin (an enzyme involved in LPA production) and Gα13 in vascular development, we suggest that LPA4 provides a link between these 2 molecules.

scholarly journals UNC-11, a Caenorhabditis elegans AP180 Homologue, Regulates the Size and Protein Composition of Synaptic Vesicles

1999 ◽  
Vol 10 (7) ◽  
pp. 2343-2360 ◽  
Author(s):  
Michael L. Nonet ◽  
Andrea M. Holgado ◽  
Faraha Brewer ◽  
Craig J. Serpe ◽  
Betty A. Norbeck ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Synaptic Vesicle ◽  
Neurotransmitter Release ◽  
Synaptic Vesicles ◽  
Adaptor Protein ◽  
Protein Composition ◽  
Mammalian Brain ◽  
Snare Protein ◽  
Vesicle Biogenesis ◽  
Clathrin Adaptor

The unc-11 gene of Caenorhabditis elegans encodes multiple isoforms of a protein homologous to the mammalian brain-specific clathrin-adaptor protein AP180. The UNC-11 protein is expressed at high levels in the nervous system and at lower levels in other tissues. In neurons, UNC-11 is enriched at presynaptic terminals but is also present in cell bodies. unc-11mutants are defective in two aspects of synaptic vesicle biogenesis. First, the SNARE protein synaptobrevin is mislocalized, no longer being exclusively localized to synaptic vesicles. The reduction of synaptobrevin at synaptic vesicles is the probable cause of the reduced neurotransmitter release observed in these mutants. Second,unc-11 mutants accumulate large vesicles at synapses. We propose that the UNC-11 protein mediates two functions during synaptic vesicle biogenesis: it recruits synaptobrevin to synaptic vesicle membranes and it regulates the size of the budded vesicle during clathrin coat assembly.

scholarly journals Extreme stiffness of neuronal synapses and implications for synaptic adhesion and plasticity

2020 ◽  
Author(s):  
Ju Yang ◽  
Nicola Mandriota ◽  
Steven Glenn Harrellson ◽  
John Anthony Jones-Molina ◽  
Rafael Yuste ◽  
...  
Keyword(s):  
Structural Changes ◽  
Neural Circuits ◽  
Neural Circuit ◽  
Critical Role ◽  
Theoretical Models ◽  
Cell Types ◽  
Long Term Potentiation ◽  
Biophysical Model ◽  
And Function ◽  
Circuit Function

AbstractSynapses play a critical role in neural circuits, and they are potential sites for learning and memory. Maintenance of synaptic adhesion is critical for neural circuit function, however, biophysical mechanisms that help maintain synaptic adhesion are not clear. Studies with various cell types demonstrated the important role of stiffness in cellular adhesions. Although synaptic stiffness could also play a role in synaptic adhesion, stiffnesses of synapses are difficult to characterize due to their small size and challenges in verifying synapse identity and function. To address these challenges, we have developed an experimental platform that combines atomic force microscopy, fluorescence microscopy, and transmission electron microscopy. Here, using this platform, we report that functional, mature, excitatory synapses had an average elastic modulus of approximately 200 kPa, two orders of magnitude larger than that of the brain tissue, suggesting stiffness might have a role in synapse function. Similar to various functional and anatomical features of neural circuits, synaptic stiffness had a lognormal-like distribution, hinting a possible regulation of stiffness by processes involved in neural circuit function. In further support of this possibility, we observed that synaptic stiffness was correlated with spine size, a quantity known to correlate with synaptic strength. Using established stages of the long-term potentiation timeline and theoretical models of adhesion cluster dynamics, we developed a biophysical model of the synapse that not only explains extreme stiffness of synapses, their statistical distribution, and correlation with spine size, but also offers an explanation to how early biomolecular and structural changes during functional potentiation could lead to strengthening of synaptic adhesion. According to this model, synaptic stiffness serves as an indispensable physical messenger, feeding information back to synaptic adhesion molecules to facilitate maintenance of synaptic adhesion.

The Na+/H+ Exchanger Nhe1 Modulates Network Excitability via GABA Release

2018 ◽  
Vol 29 (10) ◽  
pp. 4263-4276 ◽  
Author(s):  
Hartmut T Bocker ◽  
Theresa Heinrich ◽  
Lutz Liebmann ◽  
J Christopher Hennings ◽  
Eric Seemann ◽  
...  
Keyword(s):  
Synaptic Vesicles ◽  
Neuronal Excitability ◽  
Ph Dependence ◽  
Gaba Release ◽  
Epileptic Activity ◽  
Inhibitory Interneurons ◽  
Gabaergic Interneurons ◽  
Glutamatergic Neurons ◽  
Brain Functions ◽  
Ph Dependent

Abstract Brain functions are extremely sensitive to pH changes because of the pH-dependence of proteins involved in neuronal excitability and synaptic transmission. Here, we show that the Na+/H+ exchanger Nhe1, which uses the Na+ gradient to extrude H+, is expressed at both inhibitory and excitatory presynapses. We disrupted Nhe1 specifically in mice either in Emx1-positive glutamatergic neurons or in parvalbumin-positive cells, mainly GABAergic interneurons. While Nhe1 disruption in excitatory neurons had no effect on overall network excitability, mice with disruption of Nhe1 in parvalbumin-positive neurons displayed epileptic activity. From our electrophysiological analyses in the CA1 of the hippocampus, we conclude that the disruption in parvalbumin-positive neurons impairs the release of GABA-loaded vesicles, but increases the size of GABA quanta. The latter is most likely an indirect pH-dependent effect, as Nhe1 was not expressed in purified synaptic vesicles itself. Conclusively, our data provide first evidence that Nhe1 affects network excitability via modulation of inhibitory interneurons.

scholarly journals Clathrin-independent endocytic retrieval of SV proteins mediated by the clathrin adaptor AP-2 at mammalian central synapses

eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Tania López-Hernández ◽  
Koh-ichiro Takenaka ◽  
Yasunori Mori ◽  
Pornparn Kongpracha ◽  
Shushi Nagamori ◽  
...  
Keyword(s):  
Cell Surface ◽  
Synaptic Vesicles ◽  
Hippocampal Neurons ◽  
Adaptor Protein ◽  
The Reformation ◽  
Comprehensive Survey ◽  
Vesicular Transporters ◽  
Clathrin Adaptor ◽  
Central Synapses

Neurotransmission is based on the exocytic fusion of synaptic vesicles (SVs) followed by endocytic membrane retrieval and the reformation of SVs. Conflicting models have been proposed regarding the mechanisms of SV endocytosis, most notably clathrin/adaptor protein complex 2 (AP-2)-mediated endocytosis and clathrin-independent ultrafast endocytosis. Partitioning between these pathways has been suggested to be controlled by temperature and stimulus paradigm. We report on the comprehensive survey of six major SV proteins to show that SV endocytosis in mouse hippocampal neurons at physiological temperature occurs independent of clathrin while the endocytic retrieval of a subset of SV proteins including the vesicular transporters for glutamate and GABA depend on sorting by the clathrin adaptor AP-2. Our findings highlight a clathrin-independent role of the clathrin adaptor AP-2 in the endocytic retrieval of select SV cargos from the presynaptic cell surface and suggest a revised model for the endocytosis of SV membranes at mammalian central synapses.

scholarly journals Deletion of ErbB4 Disrupts Synaptic Transmission and Long-Term Potentiation of Thalamic Input to Amygdalar Medial Paracapsular Intercalated Cells

2021 ◽  
Vol 13 ◽  
Author(s):  
Douglas Asede ◽  
James Okoh ◽  
Sabah Ali ◽  
Divyesh Doddapaneni ◽  
M. McLean Bolton
Keyword(s):  
Synaptic Transmission ◽  
Critical Role ◽  
Inhibitory Neuron ◽  
Long Term Potentiation ◽  
Learning Mechanisms ◽  
Disease Etiology ◽  
Term Potentiation ◽  
And Function ◽  
The Impact

Identification of candidate risk genes and alteration in the expression of proteins involved in regulating inhibitory neuron function in various psychiatric disorders, support the notion that GABAergic neuron dysfunction plays an important role in disease etiology. Genetic variations in neuregulin and its receptor kinase ErbB4, expressed exclusively by GABAergic neurons in the CNS, have been linked with schizophrenia. In the amygdala, ErbB4 is highly expressed in GABAergic intercalated cell clusters (ITCs), which play a critical role in amygdala-dependent behaviors. It is however unknown whether ErbB4 deletion from ITCs affects their synaptic properties and function in amygdala circuitry. Here, we examined the impact of ErbB4 deletion on inhibitory and excitatory circuits recruiting medial paracapsular ITCs (mpITCs) using electrophysiological techniques. Ablation of ErbB4 in mpITCs suppressed NMDA receptor-mediated synaptic transmission at thalamo-mpITC synapses and enhanced thalamic driven GABAergic transmission onto mpITCs. Furthermore, long-term potentiation (LTP) at thalamo-mpITC synapses was compromised in ErbB4 mutant mice, indicating that ErbB4 activity is critical for LTP at these synapses. Together, our findings suggest that ErbB4 deletion from mpITCs disrupts excitation-inhibition balance and learning mechanisms in amygdala circuits.

The Laryngeal Epithelium in Reflux

2011 ◽  
Vol 21 (3) ◽  
pp. 112-117 ◽  
Author(s):  
Elizabeth Erickson-Levendoski ◽  
Mahalakshmi Sivasankar
Keyword(s):  
Laryngopharyngeal Reflux ◽  
Critical Role ◽  
Structure And Function ◽  
Laryngeal Disease ◽  
Health And Disease ◽  
And Function ◽  
The Impact

The epithelium plays a critical role in the maintenance of laryngeal health. This is evident in that laryngeal disease may result when the integrity of the epithelium is compromised by insults such as laryngopharyngeal reflux. In this article, we will review the structure and function of the laryngeal epithelium and summarize the impact of laryngopharyngeal reflux on the epithelium. Research investigating the ramifications of reflux on the epithelium has improved our understanding of laryngeal disease associated with laryngopharyngeal reflux. It further highlights the need for continued research on the laryngeal epithelium in health and disease.

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