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1.
Neuron ; 110(20): 3302-3317.e7, 2022 10 19.
Artículo en Inglés | MEDLINE | ID: mdl-36070750

RESUMEN

Homeostatic plasticity (HP) encompasses a suite of compensatory physiological processes that counteract neuronal perturbations, enabling brain resilience. Currently, we lack a complete description of the homeostatic processes that operate within the mammalian brain. Here, we demonstrate that acute, partial AMPAR-specific antagonism induces potentiation of presynaptic neurotransmitter release in adult hippocampus, a form of compensatory plasticity that is consistent with the expression of presynaptic homeostatic plasticity (PHP) documented at peripheral synapses. We show that this compensatory plasticity can be induced within minutes, requires postsynaptic NMDARs, and is expressed via correlated increases in dendritic spine volume, active zone area, and docked vesicle number. Further, simultaneous postsynaptic genetic reduction of GluA1, GluA2, and GluA3 in triple heterozygous knockouts induces potentiation of presynaptic release. Finally, induction of compensatory plasticity at excitatory synapses induces a parallel, NMDAR-dependent potentiation of inhibitory transmission, a cross-modal effect consistent with the anti-epileptic activity of AMPAR-specific antagonists used in humans.


Asunto(s)
Receptores de N-Metil-D-Aspartato , Sinapsis , Humanos , Animales , Sinapsis/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Hipocampo/fisiología , Homeostasis/fisiología , Neurotransmisores/metabolismo , Plasticidad Neuronal/fisiología , Mamíferos/metabolismo
2.
Neuron ; 110(22): 3743-3759.e6, 2022 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-36087584

RESUMEN

Presynaptic homeostatic plasticity (PHP) adaptively regulates synaptic transmission in health and disease. Despite identification of numerous genes that are essential for PHP, we lack a dynamic framework to explain how PHP is initiated, potentiated, and limited to achieve precise control of vesicle fusion. Here, utilizing both mice and Drosophila, we demonstrate that PHP progresses through the assembly and physical expansion of presynaptic signaling foci where activated integrins biochemically converge with trans-synaptic Semaphorin2b/PlexinB signaling. Each component of the identified signaling complexes, including alpha/beta-integrin, Semaphorin2b, PlexinB, talin, and focal adhesion kinase (FAK), and their biochemical interactions, are essential for PHP. Complex integrity requires the Sema2b ligand and complex expansion includes a ∼2.5-fold expansion of active-zone associated puncta composed of the actin-binding protein talin. Finally, complex pre-expansion is sufficient to accelerate the rate and extent of PHP. A working model is proposed incorporating signal convergence with dynamic molecular assemblies that instruct PHP.


Asunto(s)
Proteínas de Drosophila , Animales , Ratones , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/fisiología , Terminales Presinápticos/metabolismo , Talina/metabolismo , Plasticidad Neuronal/fisiología , Drosophila/metabolismo
3.
Nat Commun ; 12(1): 513, 2021 01 21.
Artículo en Inglés | MEDLINE | ID: mdl-33479240

RESUMEN

Missense mutations in Valosin-Containing Protein (VCP) are linked to diverse degenerative diseases including IBMPFD, amyotrophic lateral sclerosis (ALS), muscular dystrophy and Parkinson's disease. Here, we characterize a VCP-binding co-factor (SVIP) that specifically recruits VCP to lysosomes. SVIP is essential for lysosomal dynamic stability and autophagosomal-lysosomal fusion. SVIP mutations cause muscle wasting and neuromuscular degeneration while muscle-specific SVIP over-expression increases lysosomal abundance and is sufficient to extend lifespan in a context, stress-dependent manner. We also establish multiple links between SVIP and VCP-dependent disease in our Drosophila model system. A biochemical screen identifies a disease-causing VCP mutation that prevents SVIP binding. Conversely, over-expression of an SVIP mutation that prevents VCP binding is deleterious. Finally, we identify a human SVIP mutation and confirm the pathogenicity of this mutation in our Drosophila model. We propose a model for VCP disease based on the differential, co-factor-dependent recruitment of VCP to intracellular organelles.


Asunto(s)
Longevidad/genética , Lisosomas/metabolismo , Proteínas de la Membrana/genética , Mutación , Enfermedades Neurodegenerativas/genética , Proteínas de Unión a Fosfato/genética , Proteína que Contiene Valosina/genética , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Animales , Animales Modificados Genéticamente , Modelos Animales de Enfermedad , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Demencia Frontotemporal/genética , Demencia Frontotemporal/metabolismo , Humanos , Proteínas de la Membrana/metabolismo , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/metabolismo , Miositis por Cuerpos de Inclusión/genética , Miositis por Cuerpos de Inclusión/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Osteítis Deformante/genética , Osteítis Deformante/metabolismo , Proteínas de Unión a Fosfato/metabolismo , Unión Proteica , Proteína que Contiene Valosina/metabolismo
4.
Elife ; 92020 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-32609087

RESUMEN

We identify a set of common phenotypic modifiers that interact with five independent autism gene orthologs (RIMS1, CHD8, CHD2, WDFY3, ASH1L) causing a common failure of presynaptic homeostatic plasticity (PHP) in Drosophila. Heterozygous null mutations in each autism gene are demonstrated to have normal baseline neurotransmission and PHP. However, PHP is sensitized and rendered prone to failure. A subsequent electrophysiology-based genetic screen identifies the first known heterozygous mutations that commonly genetically interact with multiple ASD gene orthologs, causing PHP to fail. Two phenotypic modifiers identified in the screen, PDPK1 and PPP2R5D, are characterized. Finally, transcriptomic, ultrastructural and electrophysiological analyses define one mechanism by which PHP fails; an unexpected, maladaptive up-regulation of CREG, a conserved, neuronally expressed, stress response gene and a novel repressor of PHP. Thus, we define a novel genetic landscape by which diverse, unrelated autism risk genes may converge to commonly affect the robustness of synaptic transmission.


Asunto(s)
Trastorno Autístico/genética , Plasticidad Neuronal/genética , Animales , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Genes/genética , Predisposición Genética a la Enfermedad/genética , Homeostasis/genética , Humanos , Mutación/genética , Factores de Riesgo , Transmisión Sináptica/genética
5.
Neuron ; 107(1): 95-111.e6, 2020 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-32380032

RESUMEN

Progressive synapse loss is an inevitable and insidious part of age-related neurodegenerative disease. Typically, synapse loss precedes symptoms of cognitive and motor decline. This suggests the existence of compensatory mechanisms that can temporarily counteract the effects of ongoing neurodegeneration. Here, we demonstrate that presynaptic homeostatic plasticity (PHP) is induced at degenerating neuromuscular junctions, mediated by an evolutionarily conserved activity of presynaptic ENaC channels in both Drosophila and mouse. To assess the consequence of eliminating PHP in a mouse model of ALS-like degeneration, we generated a motoneuron-specific deletion of Scnn1a, encoding the ENaC channel alpha subunit. We show that Scnn1a is essential for PHP without adversely affecting baseline neural function or lifespan. However, Scnn1a knockout in a degeneration-causing mutant background accelerated motoneuron loss and disease progression to twice the rate observed in littermate controls with intact PHP. We propose a model of neuroprotective homeostatic plasticity, extending organismal lifespan and health span.


Asunto(s)
Canales Epiteliales de Sodio/metabolismo , Homeostasis/fisiología , Plasticidad Neuronal/fisiología , Neuroprotección/fisiología , Terminales Presinápticos/metabolismo , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Drosophila melanogaster , Ratones , Ratones Noqueados , Unión Neuromuscular/metabolismo
6.
Neuron ; 105(4): 591-593, 2020 02 19.
Artículo en Inglés | MEDLINE | ID: mdl-32078791

RESUMEN

In this issue of Neuron, Ashrafi et al. (2020) identify a feedforward signaling mechanism that couples neuronal activity to the homeostatic maintenance of axonal and synaptic ATP production. This mechanism is achieved via changes in cytoplasmic calcium and activation of brain-specific, mitochondrial MICU3.


Asunto(s)
Calcio , Transmisión Sináptica , Adenosina Trifosfato , Homeostasis , Neuronas
7.
Neuron ; 105(3): 491-505.e3, 2020 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-31810838

RESUMEN

Epigenetic gene regulation shapes neuronal fate in the embryonic nervous system. Post-embryonically, epigenetic signaling within neurons has been associated with impaired learning, autism, ataxia, and schizophrenia. Epigenetic factors are also enriched in glial cells. However, little is known about epigenetic signaling in glia and nothing is known about the intersection of glial epigenetic signaling and presynaptic homeostatic plasticity. During a screen for genes involved in presynaptic homeostatic synaptic plasticity, we identified an essential role for the histone acetyltransferase and deubiquitinase SAGA complex in peripheral glia. We present evidence that the SAGA complex is necessary for homeostatic plasticity, demonstrating involvement of four new genes in homeostatic plasticity. This is also evidence that glia participate in presynaptic homeostatic plasticity, invoking previously unexplored intercellular, homeostatic signaling at a tripartite synapse. We show, mechanistically, SAGA signaling regulates the composition of and signaling from the extracellular matrix during homeostatic plasticity.


Asunto(s)
Epigénesis Genética/fisiología , Homeostasis/fisiología , Neuroglía/fisiología , Plasticidad Neuronal/fisiología , Terminales Presinápticos/fisiología , Transducción de Señal/fisiología , Animales , Drosophila melanogaster
8.
Curr Biol ; 29(22): 3863-3873.e2, 2019 11 18.
Artículo en Inglés | MEDLINE | ID: mdl-31708391

RESUMEN

Presynaptic homeostatic plasticity (PHP) is an evolutionarily conserved form of adaptive neuromodulation and is observed at both central and peripheral synapses. In this work, we make several fundamental advances by interrogating the synapse specificity of PHP. We define how PHP remains robust to acute versus long-term neurotransmitter receptor perturbation. We describe a general PHP property that includes global induction and synapse-specific expression mechanisms. Finally, we detail a novel synapse-specific PHP expression mechanism that enables the conversion from short- to long-term PHP expression. If our data can be extended to other systems, including the mammalian central nervous system, they suggest that PHP can be broadly induced and expressed to sustain the function of complex neural circuitry.


Asunto(s)
Plasticidad Neuronal/fisiología , Terminales Presinápticos/fisiología , Animales , Calcio/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Potenciales Postsinápticos Excitadores/fisiología , Homeostasis/fisiología , Neurotransmisores/fisiología , Terminales Presinápticos/metabolismo , Sinapsis/fisiología , Transmisión Sináptica/fisiología , Vesículas Sinápticas/metabolismo
9.
Cell Rep ; 27(9): 2527-2536.e4, 2019 05 28.
Artículo en Inglés | MEDLINE | ID: mdl-31141679

RESUMEN

Genetically wired neural mechanisms inhibit mating between species because even naive animals rarely mate with other species. These mechanisms can evolve through changes in expression or function of key genes in sensory pathways or central circuits. Gr32a is a gustatory chemoreceptor that, in D. melanogaster, is essential to inhibit interspecies courtship and sense quinine. Similar to D. melanogaster, we find that D. simulans Gr32a is expressed in foreleg tarsi, sensorimotor appendages that inhibit interspecies courtship, and it is required to sense quinine. Nevertheless, Gr32a is not required to inhibit interspecies mating by D. simulans males. However, and similar to its function in D. melanogaster, Ppk25, a member of the Pickpocket family, promotes conspecific courtship in D. simulans. Together, we have identified distinct evolutionary mechanisms underlying chemosensory control of taste and courtship in closely related Drosophila species.


Asunto(s)
Evolución Biológica , Cortejo/psicología , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/fisiología , Drosophila simulans/fisiología , Receptores de Superficie Celular/metabolismo , Conducta Sexual Animal , Gusto/fisiología , Animales , Comunicación Celular , Células Quimiorreceptoras , Proteínas de Drosophila/genética , Femenino , Masculino , Feromonas , Receptores de Superficie Celular/genética , Reproducción
10.
Elife ; 82019 04 11.
Artículo en Inglés | MEDLINE | ID: mdl-30973325

RESUMEN

Firing rate homeostasis (FRH) stabilizes neural activity. A pervasive and intuitive theory argues that a single variable, calcium, is detected and stabilized through regulatory feedback. A prediction is that ion channel gene mutations with equivalent effects on neuronal excitability should invoke the same homeostatic response. In agreement, we demonstrate robust FRH following either elimination of Kv4/Shal protein or elimination of the Kv4/Shal conductance. However, the underlying homeostatic signaling mechanisms are distinct. Eliminating Shal protein invokes Krüppel-dependent rebalancing of ion channel gene expression including enhanced slo, Shab, and Shaker. By contrast, expression of these genes remains unchanged in animals harboring a CRISPR-engineered, Shal pore-blocking mutation where compensation is achieved by enhanced IKDR. These different homeostatic processes have distinct effects on homeostatic synaptic plasticity and animal behavior. We propose that FRH includes mechanisms of proteostatic feedback that act in parallel with activity-driven feedback, with implications for the pathophysiology of human channelopathies.


Asunto(s)
Potenciales de Acción , Retroalimentación , Neuronas/fisiología , Animales , Proteínas de Drosophila/deficiencia , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Expresión Génica , Técnicas de Inactivación de Genes , Homeostasis , Canales Iónicos/deficiencia , Canales Iónicos/metabolismo
11.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1579-1591, 2019 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-30904609

RESUMEN

Evolutionarily conserved homeostatic systems have been shown to modulate synaptic efficiency at the neuromuscular junctions of organisms. While advances have been made in identifying molecules that function presynaptically during homeostasis, limited information is currently available on how postsynaptic alterations affect presynaptic function. We previously identified a role for postsynaptic Dystrophin in the maintenance of evoked neurotransmitter release. We herein demonstrated that Dystrobrevin, a member of the Dystrophin Glycoprotein Complex, was delocalized from the postsynaptic region in the absence of Dystrophin. A newly-generated Dystrobrevin mutant showed elevated evoked neurotransmitter release, increased bouton numbers, and a readily releasable pool of synaptic vesicles without changes in the function or numbers of postsynaptic glutamate receptors. In addition, we provide evidence to show that the highly conserved Cdc42 Rho GTPase plays a key role in the postsynaptic Dystrophin/Dystrobrevin pathway for synaptic homeostasis. The present results give novel insights into the synaptic deficits underlying Duchenne Muscular Dystrophy affected by a dysfunctional Dystrophin Glycoprotein complex.


Asunto(s)
Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Proteínas Asociadas a la Distrofina/genética , Distrofina/genética , Unión Neuromuscular/genética , Proteína de Unión al GTP cdc42/genética , Animales , Animales Modificados Genéticamente , Modelos Animales de Enfermedad , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Distrofina/deficiencia , Proteínas Asociadas a la Distrofina/metabolismo , Regulación de la Expresión Génica , Homeostasis/genética , Humanos , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patología , Unión Neuromuscular/metabolismo , Unión Neuromuscular/patología , Potenciales Sinápticos/genética , Transmisión Sináptica , Vesículas Sinápticas/metabolismo , Proteína de Unión al GTP cdc42/metabolismo
12.
Elife ; 72018 11 13.
Artículo en Inglés | MEDLINE | ID: mdl-30422113

RESUMEN

Presynaptic homeostatic plasticity (PHP) compensates for impaired postsynaptic neurotransmitter receptor function through a rapid, persistent adjustment of neurotransmitter release, an effect that can exceed 200%. An unexplained property of PHP is the preservation of short-term plasticity (STP), thereby stabilizing activity-dependent synaptic information transfer. We demonstrate that the dramatic potentiation of presynaptic release during PHP is achieved while simultaneously maintaining a constant ratio of primed to super-primed synaptic vesicles, thereby preserving STP. Mechanistically, genetic, biochemical and electrophysiological evidence argue that a constant ratio of primed to super-primed synaptic vesicles is achieved by the concerted action of three proteins: Unc18, Syntaxin1A and RIM. Our data support a model based on the regulated availability of Unc18 at the presynaptic active zone, a process that is restrained by Syntaxin1A and facilitated by RIM. As such, regulated vesicle priming/super-priming enables PHP to stabilize both synaptic gain and the activity-dependent transfer of information at a synapse.


Asunto(s)
Plasticidad Neuronal , Neurotransmisores/metabolismo , Terminales Presinápticos/metabolismo , Animales , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Proteínas del Tejido Nervioso/metabolismo , Vesículas Sinápticas/metabolismo , Sintaxina 1/metabolismo , Proteínas de Unión al GTP rab3/metabolismo
13.
Neuron ; 100(5): 1163-1179.e4, 2018 12 05.
Artículo en Inglés | MEDLINE | ID: mdl-30344041

RESUMEN

We define a homeostatic function for innate immune signaling within neurons. A genetic analysis of the innate immune signaling genes IMD, IKKß, Tak1, and Relish demonstrates that each is essential for presynaptic homeostatic plasticity (PHP). Subsequent analyses define how the rapid induction of PHP (occurring in seconds) can be coordinated with the life-long maintenance of PHP, a time course that is conserved from invertebrates to mammals. We define a novel bifurcation of presynaptic innate immune signaling. Tak1 (Map3K) acts locally and is selective for rapid PHP induction. IMD, IKKß, and Relish are essential for long-term PHP maintenance. We then define how Tak1 controls vesicle release. Tak1 stabilizes the docked vesicle state, which is essential for the homeostatic expansion of the readily releasable vesicle pool. This represents a mechanism for the control of vesicle release, and an interface of innate immune signaling with the vesicle fusion apparatus and homeostatic plasticity.


Asunto(s)
Homeostasis , Inmunidad Innata , Plasticidad Neuronal/inmunología , Neuronas/inmunología , Terminales Presinápticos/inmunología , Vesículas Sinápticas/inmunología , Animales , Animales Modificados Genéticamente , Proteínas de Drosophila/inmunología , Drosophila melanogaster , Femenino , Quinasa I-kappa B/inmunología , Quinasas Quinasa Quinasa PAM/inmunología , Masculino , Transducción de Señal , Factores de Transcripción/inmunología
14.
Cell ; 174(3): 505-520, 2018 07 26.
Artículo en Inglés | MEDLINE | ID: mdl-30053424

RESUMEN

Although gene discovery in neuropsychiatric disorders, including autism spectrum disorder, intellectual disability, epilepsy, schizophrenia, and Tourette disorder, has accelerated, resulting in a large number of molecular clues, it has proven difficult to generate specific hypotheses without the corresponding datasets at the protein complex and functional pathway level. Here, we describe one path forward-an initiative aimed at mapping the physical and genetic interaction networks of these conditions and then using these maps to connect the genomic data to neurobiology and, ultimately, the clinic. These efforts will include a team of geneticists, structural biologists, neurobiologists, systems biologists, and clinicians, leveraging a wide array of experimental approaches and creating a collaborative infrastructure necessary for long-term investigation. This initiative will ultimately intersect with parallel studies that focus on other diseases, as there is a significant overlap with genes implicated in cancer, infectious disease, and congenital heart defects.


Asunto(s)
Mapeo Cromosómico/métodos , Trastornos del Neurodesarrollo/genética , Biología de Sistemas/métodos , Redes Reguladoras de Genes/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Genómica/métodos , Humanos , Neurobiología/métodos , Neuropsiquiatría
15.
Elife ; 72018 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-29303480

RESUMEN

Presynaptic homeostatic plasticity stabilizes information transfer at synaptic connections in organisms ranging from insect to human. By analogy with principles of engineering and control theory, the molecular implementation of PHP is thought to require postsynaptic signaling modules that encode homeostatic sensors, a set point, and a controller that regulates transsynaptic negative feedback. The molecular basis for these postsynaptic, homeostatic signaling elements remains unknown. Here, an electrophysiology-based screen of the Drosophila kinome and phosphatome defines a postsynaptic signaling platform that includes a required function for PI3K-cII, PI3K-cIII and the small GTPase Rab11 during the rapid and sustained expression of PHP. We present evidence that PI3K-cII localizes to Golgi-derived, clathrin-positive vesicles and is necessary to generate an endosomal pool of PI(3)P that recruits Rab11 to recycling endosomal membranes. A morphologically distinct subdivision of this platform concentrates postsynaptically where we propose it functions as a homeostatic controller for retrograde, trans-synaptic signaling.


Asunto(s)
Fosfatidilinositol 3-Quinasas Clase II/metabolismo , Plasticidad Neuronal , Terminales Presinápticos/fisiología , Transducción de Señal , Animales , Fosfatidilinositol 3-Quinasas Clase III/metabolismo , Drosophila , Proteínas de Drosophila/metabolismo , Fenómenos Electrofisiológicos , Fosfatos de Fosfatidilinositol/metabolismo , Proteínas de Unión al GTP rab/metabolismo
16.
Proc Natl Acad Sci U S A ; 114(39): E8174-E8183, 2017 09 26.
Artículo en Inglés | MEDLINE | ID: mdl-28893998

RESUMEN

The circuitry of the brain is characterized by cell heterogeneity, sprawling cellular anatomy, and astonishingly complex patterns of connectivity. Determining how complex neural circuits control behavior is a major challenge that is often approached using surgical, chemical, or transgenic approaches to ablate neurons. However, all these approaches suffer from a lack of precise spatial and temporal control. This drawback would be overcome if cellular ablation could be controlled with light. Cells are naturally and cleanly ablated through apoptosis due to the terminal activation of caspases. Here, we describe the engineering of a light-activated human caspase-3 (Caspase-LOV) by exploiting its natural spring-loaded activation mechanism through rational insertion of the light-sensitive LOV2 domain that expands upon illumination. We apply the light-activated caspase (Caspase-LOV) to study neurodegeneration in larval and adult Drosophila Using the tissue-specific expression system (UAS)-GAL4, we express Caspase-LOV specifically in three neuronal cell types: retinal, sensory, and motor neurons. Illumination of whole flies or specific tissues containing Caspase-LOV-induced cell death and allowed us to follow the time course and sequence of neurodegenerative events. For example, we find that global synchronous activation of caspase-3 drives degeneration with a different time-course and extent in sensory versus motor neurons. We believe the Caspase-LOV tool we engineered will have many other uses for neurobiologists and others for specific temporal and spatial ablation of cells in complex organisms.


Asunto(s)
Apoptosis/fisiología , Caspasa 3/genética , Drosophila melanogaster/metabolismo , Activación Enzimática/genética , Luz , Neuronas Motoras/metabolismo , Células Receptoras Sensoriales/metabolismo , Técnicas de Ablación , Animales , Animales Modificados Genéticamente , Encéfalo/fisiología , Caspasa 3/metabolismo , Caspasas/genética , Proteínas de Unión al ADN/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Conducción Nerviosa/fisiología , Interferencia de ARN , ARN Interferente Pequeño/genética , Proteínas Virales/metabolismo
17.
Nature ; 550(7674): 109-113, 2017 10 05.
Artículo en Inglés | MEDLINE | ID: mdl-28953869

RESUMEN

Homeostatic signalling systems ensure stable but flexible neural activity and animal behaviour. Presynaptic homeostatic plasticity is a conserved form of neuronal homeostatic signalling that is observed in organisms ranging from Drosophila to human. Defining the underlying molecular mechanisms of neuronal homeostatic signalling will be essential in order to establish clear connections to the causes and progression of neurological disease. During neural development, semaphorin-plexin signalling instructs axon guidance and neuronal morphogenesis. However, semaphorins and plexins are also expressed in the adult brain. Here we show that semaphorin 2b (Sema2b) is a target-derived signal that acts upon presynaptic plexin B (PlexB) receptors to mediate the retrograde, homeostatic control of presynaptic neurotransmitter release at the neuromuscular junction in Drosophila. Further, we show that Sema2b-PlexB signalling regulates presynaptic homeostatic plasticity through the cytoplasmic protein Mical and the oxoreductase-dependent control of presynaptic actin. We propose that semaphorin-plexin signalling is an essential platform for the stabilization of synaptic transmission throughout the developing and mature nervous system. These findings may be relevant to the aetiology and treatment of diverse neurological and psychiatric diseases that are characterized by altered or inappropriate neural function and behaviour.


Asunto(s)
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Homeostasis , Proteínas del Tejido Nervioso/metabolismo , Plasticidad Neuronal , Receptores de Superficie Celular/metabolismo , Semaforinas/metabolismo , Transducción de Señal , Actinas/metabolismo , Animales , Proteínas de Unión al ADN/metabolismo , Femenino , Masculino , Unión Neuromuscular/metabolismo , Neurotransmisores/metabolismo , Terminales Presinápticos/metabolismo , Receptores Presinapticos/metabolismo , Transmisión Sináptica , Vesículas Sinápticas/metabolismo
18.
Cell Rep ; 20(8): 1855-1866, 2017 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-28834749

RESUMEN

The homeostatic control of presynaptic neurotransmitter release stabilizes information transfer at synaptic connections in the nervous system of organisms ranging from insect to human. Presynaptic homeostatic signaling centers upon the regulated membrane insertion of an amiloride-sensitive degenerin/epithelial sodium (Deg/ENaC) channel. Elucidating the subunit composition of this channel is an essential step toward defining the underlying mechanisms of presynaptic homeostatic plasticity (PHP). Here, we demonstrate that the ppk1 gene encodes an essential subunit of this Deg/ENaC channel, functioning in motoneurons for the rapid induction and maintenance of PHP. We provide genetic and biochemical evidence that PPK1 functions together with PPK11 and PPK16 as a presynaptic, hetero-trimeric Deg/ENaC channel. Finally, we highlight tight control of Deg/ENaC channel expression and activity, showing increased PPK1 protein expression during PHP and evidence for signaling mechanisms that fine tune the level of Deg/ENaC activity during PHP.


Asunto(s)
Aminobutiratos/metabolismo , Proteínas de Drosophila/metabolismo , Canales Epiteliales de Sodio/metabolismo , Animales , Drosophila melanogaster , Femenino , Homeostasis , Masculino , Transducción de Señal , Canales de Sodio/metabolismo
19.
Elife ; 62017 05 09.
Artículo en Inglés | MEDLINE | ID: mdl-28485711

RESUMEN

Presynaptic homeostatic plasticity (PHP) controls synaptic transmission in organisms from Drosophila to human and is hypothesized to be relevant to the cause of human disease. However, the underlying molecular mechanisms of PHP are just emerging and direct disease associations remain obscure. In a forward genetic screen for mutations that block PHP we identified mctp (Multiple C2 Domain Proteins with Two Transmembrane Regions). Here we show that MCTP localizes to the membranes of the endoplasmic reticulum (ER) that elaborate throughout the soma, dendrites, axon and presynaptic terminal. Then, we demonstrate that MCTP functions downstream of presynaptic calcium influx with separable activities to stabilize baseline transmission, short-term release dynamics and PHP. Notably, PHP specifically requires the calcium coordinating residues in each of the three C2 domains of MCTP. Thus, we propose MCTP as a novel, ER-localized calcium sensor and a source of calcium-dependent feedback for the homeostatic stabilization of neurotransmission.


Asunto(s)
Calcio/metabolismo , Plasticidad Neuronal , Neuronas/fisiología , Transmisión Sináptica , Animales , Línea Celular , Drosophila
20.
Neuron ; 92(3): 632-636, 2016 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-27810007

RESUMEN

The greatest challenge in moving neuroscience research forward in the 21st century is recruiting, training, and retaining the brightest, rigorous, and most diverse scientists. The MBL research training courses Neurobiology and Neural Systems & Behavior, and the Summer Program in Neuroscience, Excellence, and Success provide a model for full immersion, discovery-based training while enhancing cultural, geographic, and racial diversity.


Asunto(s)
Academias e Institutos/organización & administración , Neurociencias/educación , Humanos
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