RESUMEN
Long-term sensitization of the gill withdrawal reflex in Aplysia requires heterosynaptic, modulatory input that is mediated in part by the growth of new synaptic connections between sensory neurons and their follower cells (intrinsic mediating circuit). Whether modulatory interneurons (the extrinsic modulatory circuit) also display learning-related structural synaptic plasticity remains unknown. To test this idea, we added a bona fide serotonergic modulatory neuron, the metacerebral cell (MCC), to sensory-motor neuron co-cultures and examined the modulating presynaptic varicosities of MCCs before and after repeated pulses of serotonin (5-HT) that induced long-term facilitation (LTF). We observed robust growth of new serotonergic varicosities that were positive for serotonin and capable of synaptic recycling. Our findings demonstrate that, in addition to structural changes in the intrinsic mediating circuit, there are also significant learning-related structural changes in the extrinsic modulating circuit, and these changes might provide a cellular mechanism for savings and for spread of memory.
Asunto(s)
Aplysia/fisiología , Interneuronas/fisiología , Plasticidad Neuronal/fisiología , Células Receptoras Sensoriales/citología , Células Receptoras Sensoriales/fisiología , Neuronas Serotoninérgicas/citología , Serotonina/farmacología , Animales , Aplysia/efectos de los fármacos , Técnicas de Cocultivo , Exocitosis/efectos de los fármacos , Neuronas Motoras/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Reflejo , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/metabolismo , Neuronas Serotoninérgicas/efectos de los fármacos , Sinapsis/fisiologíaRESUMEN
GABAergic signaling in the amygdala controls learned fear, and its dysfunction potentially contributes to posttraumatic stress disorder (PTSD). We find that sub-threshold fear conditioning leads to dopamine receptor D4-dependent long-term depression (LTD) of glutamatergic excitatory synapses by increasing inhibitory inputs onto neurons of the dorsal intercalated cell mass (ITC) in the amygdala. Pharmacological, genetic, and optogenetic manipulations of the amygdala regions centered on the dorsal ITC reveal that this LTD limits less salient experiences from forming persistent memories. In further support of the idea that LTD has preventive and discriminative roles, we find that LTD at the dorsal ITC is impaired in mice exhibiting PTSD-like behaviors. These findings reveal a novel role of inhibitory circuits in the amygdala, which serves to dampen and restrict the level of fear expression. This mechanism is interfered with by stimuli that give rise to PTSD and may also be recruited for fear-related psychiatric diseases.
Asunto(s)
Amígdala del Cerebelo/fisiología , Miedo/fisiología , Aprendizaje/fisiología , Red Nerviosa/fisiología , Inhibición Neural/fisiología , Receptores de Dopamina D4/fisiología , Animales , Dopamina/fisiología , Miedo/psicología , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Plasticidad Neuronal/fisiología , Técnicas de Cultivo de ÓrganosRESUMEN
Consolidation of implicit memory in the invertebrate Aplysia and explicit memory in the mammalian hippocampus are associated with remodeling and growth of preexisting synapses and the formation of new synapses. Here, we compare and contrast structural components of the synaptic plasticity that underlies these two distinct forms of memory. In both cases, the structural changes involve time-dependent processes. Thus, some modifications are transient and may contribute to early formative stages of long-term memory, whereas others are more stable, longer lasting, and likely to confer persistence to memory storage. In addition, we explore the possibility that trans-synaptic signaling mechanisms governing de novo synapse formation during development can be reused in the adult for the purposes of structural synaptic plasticity and memory storage. Finally, we discuss how these mechanisms set in motion structural rearrangements that prepare a synapse to strengthen the same memory and, perhaps, to allow it to take part in other memories as a basis for understanding how their anatomical representation results in the enhanced expression and storage of memories in the brain.
Asunto(s)
Aplysia/fisiología , Memoria/fisiología , Modelos Neurológicos , Plasticidad Neuronal , Animales , Espinas Dendríticas/fisiología , Espinas Dendríticas/ultraestructura , Hipocampo/fisiología , Hipocampo/ultraestructura , Transducción de Señal , Sinapsis/fisiología , Sinapsis/ultraestructuraRESUMEN
Neurotrophins control the development and adult plasticity of the vertebrate nervous system. Failure to identify invertebrate neurotrophin orthologs, however, has precluded studies in invertebrate models, limiting our understanding of fundamental aspects of neurotrophin biology and function. We identified a neurotrophin (ApNT) and Trk receptor (ApTrk) in the mollusk Aplysia and found that they play a central role in learning-related synaptic plasticity. Blocking ApTrk signaling impairs long-term facilitation, whereas augmenting ApNT expression enhances it and induces the growth of new synaptic varicosities at the monosynaptic connection between sensory and motor neurons of the gill-withdrawal reflex. Unlike vertebrate neurotrophins, ApNT has multiple coding exons and exerts distinct synaptic effects through differentially processed and secreted splice isoforms. Our findings demonstrate the existence of bona fide neurotrophin signaling in invertebrates and reveal a posttranscriptional mechanism that regulates neurotrophin processing and the release of proneurotrophins and mature neurotrophins that differentially modulate synaptic plasticity.
Asunto(s)
Factores de Crecimiento Nervioso/metabolismo , Sinapsis/metabolismo , Empalme Alternativo , Secuencia de Aminoácidos , Animales , Aplysia , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Células Cultivadas , Técnicas de Cocultivo , Células HEK293 , Humanos , Datos de Secuencia Molecular , Neuronas Motoras/citología , Neuronas Motoras/metabolismo , Factores de Crecimiento Nervioso/química , Factores de Crecimiento Nervioso/genética , Plasticidad Neuronal , Células PC12 , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Ratas , Receptor trkA/química , Receptor trkA/genética , Receptor trkA/metabolismo , Células Receptoras Sensoriales/citología , Células Receptoras Sensoriales/metabolismo , Serotonina/farmacología , Transducción de Señal/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacosRESUMEN
Long-term facilitation in Aplysia is accompanied by the growth of new synaptic connections between the sensory and motor neurons of the gill-withdrawal reflex. One of the initial steps leading to the growth of these synapses is the internalization, induced by 5-HT, of the transmembrane isoform of Aplysia cell-adhesion molecule (TM-apCAM) from the plasma membrane of sensory neurons (Bailey et al., 1992). However, the mechanisms that govern the internalization of TM-apCAM and how this internalization is coupled to the molecular events that initiate the structural changes are not fully understood. Here, we report that the synthesis of membrane phosphatidylinositol 4,5-bisphosphate [PI(4,5)P(2)], which is known to be mediated by a signaling cascade through Aplysia Sec7 protein (ApSec7) and phosphatidylinositol-4-phosphate 5-kinase type I α (PIP5KIα) is required for both the internalization of TM-apCAM and the initiation of synaptic growth during 5-HT-induced long-term facilitation. Pharmacological blockade of PI(4,5)P(2) synthesis by the application of the inhibitor phenylarsine oxide blocked the internalization of apCAM. Furthermore, perturbation of the endogenous activation of ApSec7 and its downstream target PIP5KIα also blocked 5-HT-mediated internalization of TM-apCAM and synaptic growth. Finally, long-term facilitation was specifically impaired by blocking the ApSec7 signaling pathway at sensory-to-motor neuron synapses. These data indicate that the ApSec7/PIP5KIα signaling pathway is actively recruited during learning-related 5-HT signaling and acts as a key regulator of apCAM internalization associated with the formation of new synaptic connections during long-term facilitation.
Asunto(s)
Aplysia/fisiología , Vías Biosintéticas/fisiología , Moléculas de Adhesión Celular/fisiología , Aprendizaje/fisiología , Fosfatidilinositol 4,5-Difosfato/biosíntesis , Fosfatidilinositol 4,5-Difosfato/fisiología , Sinapsis/fisiología , 1-Fosfatidilinositol 4-Quinasa/metabolismo , Secuencia de Aminoácidos , Animales , Membrana Celular/fisiología , Clonación Molecular , Técnicas de Cocultivo , Factores de Intercambio de Guanina Nucleótido/fisiología , Inmunohistoquímica , Potenciación a Largo Plazo/fisiología , Microinyecciones , Datos de Secuencia Molecular , Mutación/genética , Mutación/fisiología , Neuritas/fisiología , Técnicas de Placa-Clamp , Reacción en Cadena en Tiempo Real de la Polimerasa , Células Receptoras Sensoriales/fisiología , Serotonina/farmacología , Transducción de Señal/fisiologíaRESUMEN
The memory reconsolidation hypothesis suggests that a memory trace becomes labile after retrieval and needs to be reconsolidated before it can be stabilized. However, it is unclear from earlier studies whether the same synapses involved in encoding the memory trace are those that are destabilized and restabilized after the synaptic reactivation that accompanies memory retrieval, or whether new and different synapses are recruited. To address this issue, we studied a simple nonassociative form of memory, long-term sensitization of the gill- and siphon-withdrawal reflex in Aplysia, and its cellular analog, long-term facilitation at the sensory-to-motor neuron synapse. We found that after memory retrieval, behavioral long-term sensitization in Aplysia becomes labile via ubiquitin/proteasome-dependent protein degradation and is reconsolidated by means of de novo protein synthesis. In parallel, we found that on the cellular level, long-term facilitation at the sensory-to-motor neuron synapse that mediates long-term sensitization is also destabilized by protein degradation and is restabilized by protein synthesis after synaptic reactivation, a procedure that parallels memory retrieval or retraining evident on the behavioral level. These results provide direct evidence that the same synapses that store the long-term memory trace encoded by changes in the strength of synaptic connections critical for sensitization are disrupted and reconstructed after signal retrieval.
Asunto(s)
Memoria/fisiología , Neuronas Motoras/fisiología , Células Receptoras Sensoriales/fisiología , Sinapsis/fisiología , Animales , Aplysia , Conducta Animal/fisiología , Células Cultivadas , Técnicas de Cocultivo , Electrochoque , Potenciales Postsinápticos Excitadores/fisiología , Miedo/fisiología , Branquias/inervación , Memoria/efectos de los fármacos , Modelos Animales , Neuronas Motoras/citología , Proteínas del Tejido Nervioso/biosíntesis , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Reflejo/fisiología , Células Receptoras Sensoriales/citología , Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacologíaRESUMEN
Neurexin and neuroligin, which undergo heterophilic interactions with each other at the synapse, are mutated in some patients with autism spectrum disorder, a set of disorders characterized by deficits in social and emotional learning. We have explored the role of neurexin and neuroligin at sensory-to-motor neuron synapses of the gill-withdrawal reflex in Aplysia, which undergoes sensitization, a simple form of learned fear. We find that depleting neurexin in the presynaptic sensory neuron or neuroligin in the postsynaptic motor neuron abolishes both long-term facilitation and the associated presynaptic growth induced by repeated pulses of serotonin. Moreover, introduction into the motor neuron of the R451C mutation of neuroligin-3 linked to autism spectrum disorder blocks both intermediate-term and long-term facilitation. Our results suggest that activity-dependent regulation of the neurexin-neuroligin interaction may govern transsynaptic signaling required for the storage of long-term memory, including emotional memory that may be impaired in autism spectrum disorder.
Asunto(s)
Moléculas de Adhesión Celular Neuronal/metabolismo , Potenciación a Largo Plazo/fisiología , Proteínas de la Membrana/metabolismo , Neuronas Motoras/fisiología , Proteínas del Tejido Nervioso/metabolismo , Receptores de Superficie Celular/metabolismo , Células Receptoras Sensoriales/fisiología , Análisis de Varianza , Animales , Aplysia , Arginina/genética , Moléculas de Adhesión Celular Neuronal/genética , Células Cultivadas , Sistema Nervioso Central/citología , Clonación Molecular/métodos , Cisteína/genética , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Proteínas Fluorescentes Verdes/genética , Humanos , Potenciación a Largo Plazo/efectos de los fármacos , Proteínas de la Membrana/genética , Microinyecciones/métodos , Datos de Secuencia Molecular , Neuronas Motoras/efectos de los fármacos , Mutación/genética , Proteínas del Tejido Nervioso/genética , Oligodesoxirribonucleótidos Antisentido/farmacología , Unión Proteica/fisiología , Receptores de Superficie Celular/genética , Células Receptoras Sensoriales/efectos de los fármacos , Serotonina/farmacología , Sinapsis/metabolismo , Sinapsis/fisiologíaRESUMEN
Despite considerable evidence for a critical role of neuroligin-1 in the specification of excitatory synapses, the cellular mechanisms and physiological roles of neuroligin-1 in mature neural circuits are poorly understood. In mutant mice deficient in neuroligin-1, or adult rats in which neuroligin-1 was depleted, we have found that neuroligin-1 stabilizes the NMDA receptors residing in the postsynaptic membrane of amygdala principal neurons, which allows for a normal range of NMDA receptor-mediated synaptic transmission. We observed marked decreases in NMDA receptor-mediated synaptic currents at afferent inputs to the amygdala of neuroligin-1 knockout mice. However, the knockout mice exhibited a significant impairment in spike-timing-dependent long-term potentiation (STD-LTP) at the thalamic but not the cortical inputs to the amygdala. Subsequent electrophysiological analyses indicated that STD-LTP in the cortical pathway is largely independent of activation of postsynaptic NMDA receptors. These findings suggest that neuroligin-1 can modulate, in a pathway-specific manner, synaptic plasticity in the amygdala circuits of adult animals, likely by regulating the abundance of postsynaptic NMDA receptors.
Asunto(s)
Amígdala del Cerebelo/fisiología , Moléculas de Adhesión Celular Neuronal/fisiología , Plasticidad Neuronal/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Transmisión Sináptica/fisiología , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Potenciales de Acción , Amígdala del Cerebelo/metabolismo , Animales , Western Blotting , Moléculas de Adhesión Celular Neuronal/genética , Moléculas de Adhesión Celular Neuronal/metabolismo , Línea Celular , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores , Humanos , Potenciación a Largo Plazo , Ratones , Ratones Noqueados , Interferencia de ARN , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Tálamo/metabolismo , Tálamo/fisiologíaRESUMEN
Transsynaptic interactions between neurons are essential during both developmental and learning-related synaptic growth. We have used Aplysia neuronal cultures to examine the contribution of transsynaptic signals in both types of synapse formation. We find that during de novo synaptogenesis, specific presynaptic innervation is required for the clustering of postsynaptic AMPA-like but not NMDA-like receptors. We further find that the cell adhesion molecule Dscam is involved in these transsynaptic interactions. Inhibition of Dscam either pre- or postsynaptically abolishes the emergence of synaptic transmission and the clustering of AMPA-like receptors. Remodeling of both AMPA-like and NMDA-like receptors also occurs during learning-related synapse formation and again requires the reactivation of Dscam-mediated transsynaptic interactions. Taken together, these findings suggest that learning-induced synapse formation recapitulates, at least in part, aspects of the mechanisms that govern de novo synaptogenesis.
Asunto(s)
Aplysia/metabolismo , Moléculas de Adhesión Celular Neuronal/fisiología , Aprendizaje/fisiología , Plasticidad Neuronal/fisiología , Receptores de Glutamato/fisiología , Sinapsis/fisiología , Animales , Técnicas de Cocultivo , Electrofisiología , Potenciales Postsinápticos Excitadores/fisiología , Conos de Crecimiento/fisiología , Inmunohistoquímica , Potenciación a Largo Plazo/fisiología , Neuronas/metabolismo , Receptores AMPA/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Receptores Presinapticos/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Serotonina/farmacología , Transducción de Señal/fisiología , Sinapsis/metabolismoRESUMEN
The time course of the requirement for local protein synthesis in the stabilization of learning-related synaptic growth and the persistence of long-term memory was examined using Aplysia bifurcated sensory neuron-motor neuron cultures. We find that, following repeated pulses of serotonin (5-HT), the local perfusion of emetine, an inhibitor of protein synthesis, or a TAT-AS oligonucleotide directed against ApCPEB blocks long-term facilitation (LTF) at either 24 or 48 hr and leads to a selective retraction of newly formed sensory neuron varicosities induced by 5-HT. By contrast, later inhibition of local protein synthesis, at 72 hr after 5-HT, has no effect on either synaptic growth or LTF. These results define a specific stabilization phase for the storage of long-term memory during which newly formed varicosities are labile and require sustained CPEB-dependent local protein synthesis to acquire the more stable properties of mature varicosities required for the persistence of LTF.
Asunto(s)
Potenciación a Largo Plazo/fisiología , Memoria/fisiología , Neuronas Motoras/metabolismo , Neuronas Aferentes/metabolismo , Biosíntesis de Proteínas/fisiología , Adaptación Fisiológica/efectos de los fármacos , Animales , Aplysia , Células Cultivadas , Emetina/farmacología , Potenciación a Largo Plazo/efectos de los fármacos , Neuronas Motoras/efectos de los fármacos , Neuronas Aferentes/efectos de los fármacos , Biosíntesis de Proteínas/efectos de los fármacos , Inhibidores de la Síntesis de la Proteína/farmacología , Serotonina/fisiología , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Factores de TiempoRESUMEN
Whereas the induction of short-term memory involves only covalent modifications of constitutively expressed preexisting proteins, the formation of long-term memory requires gene expression, new RNA, and new protein synthesis. On the cellular level, transcriptional regulation is thought to be the starting point for a series of molecular steps necessary for both the initiation and maintenance of long-term synaptic facilitation (LTF). The core molecular features of transcriptional regulation involved in the long-term process are evolutionally conserved in Aplysia, Drosophila, and mouse, and indicate that gene regulation by the cyclic AMP response element binding protein (CREB) acting in conjunction with different combinations of transcriptional factors is critical for the expression of many forms of long-term memory. In the marine snail Aplysia, the molecular mechanisms that underlie the storage of long-term memory have been extensively studied in the monosynaptic connections between identified sensory neuron and motor neurons of the gill-withdrawal reflex. One tail shock or one pulse of serotonin (5-HT), a modulatory transmitter released by tail shocks, produces a transient facilitation mediated by the cAMP-dependent protein kinase leading to covalent modifications in the sensory neurons that results in an enhancement of transmitter release and a strengthening of synaptic connections lasting minutes. By contrast, repeated pulses of 5-hydroxytryptamine (5-HT) induce a transcription- and translation-dependent long-term facilitation (LTF) lasting more than 24 h and trigger the activation of a family of transcription factors in the presynaptic sensory neurons including ApCREB1, ApCREB2 and ApC/EBP. In addition, we have recently identified novel transcription factors that modulate the expression of ApC/EBP and also are critically involved in LTF. In this review, we examine the roles of these transcription factors during consolidation of LTF induced by different stimulation paradigms.
Asunto(s)
Aplysia/genética , Aplysia/fisiología , Regulación de la Expresión Génica , Memoria a Largo Plazo/fisiología , Agua de Mar , Caracoles/genética , Transcripción Genética , Animales , Organismos Acuáticos/genética , Organismos Acuáticos/fisiologíaRESUMEN
Neuroligin-1 is a potent trigger for the de novo formation of synaptic connections, and it has recently been suggested that it is required for the maturation of functionally competent excitatory synapses. Despite evidence for the role of neuroligin-1 in specifying excitatory synapses, the underlying molecular mechanisms and physiological consequences that neuroligin-1 may have at mature synapses of normal adult animals remain unknown. By silencing endogenous neuroligin-1 acutely in the amygdala of live behaving animals, we have found that neuroligin-1 is required for the storage of associative fear memory. Subsequent cellular physiological studies showed that suppression of neuroligin-1 reduces NMDA receptor-mediated currents and prevents the expression of long-term potentiation without affecting basal synaptic connectivity at the thalamo-amygdala pathway. These results indicate that persistent expression of neuroligin-1 is required for the maintenance of NMDAR-mediated synaptic transmission, which enables normal development of synaptic plasticity and long-term memory in the amygdala of adult animals.
Asunto(s)
Amígdala del Cerebelo/metabolismo , Miedo/fisiología , Potenciación a Largo Plazo , Proteínas de la Membrana/metabolismo , Memoria/fisiología , Proteínas del Tejido Nervioso/metabolismo , Amígdala del Cerebelo/citología , Animales , Moléculas de Adhesión Celular Neuronal , Activación del Canal Iónico , Masculino , Proteínas de la Membrana/deficiencia , Proteínas del Tejido Nervioso/deficiencia , Células Piramidales/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Transmisión Sináptica , Tálamo/metabolismoRESUMEN
Synaptic remodeling and synaptic growth accompany various forms of long-term memory. Storage of the long-term memory for sensitization of the gill-withdrawal reflex in Aplysia has been extensively studied in this respect and is associated with the growth of new synapses by the sensory neurons onto their postsynaptic target neurons. Recent time-lapse imaging studies of living sensory-to-motor neuron synapses in culture have monitored both functional and structural changes simultaneously so as to follow remodeling and growth at the same specific synaptic connections continuously over time and to examine the functional contribution of these learning-related structural changes to the different time-dependent phases of memory storage. Insights provided by these studies suggest the synaptic differentiation and growth induced by learning in the mature nervous system are highly dynamic and often rapid processes that can recruit both molecules and mechanisms used for de novo synapse formation during development.
Asunto(s)
Aplysia/fisiología , Memoria/fisiología , Plasticidad Neuronal/fisiología , Sinapsis/fisiología , Animales , Transporte Axonal , Conducta Animal , Potenciación a Largo Plazo , Modelos BiológicosRESUMEN
Repeated pulses of serotonin (5-HT) induce long-term facilitation (LTF) of the synapses between sensory and motor neurons of the gill-withdrawal reflex in Aplysia. To explore how apCAM downregulation at the plasma membrane and CREB-mediated transcription in the nucleus, both of which are required for the formation of LTF, might relate to each other, we cloned an apCAM-associated protein (CAMAP) by yeast two-hybrid screening. We found that 5-HT signaling at the synapse activates PKA which in turn phosphorylates CAMAP to induce the dissociation of CAMAP from apCAM and the subsequent translocation of CAMAP into the nucleus of sensory neurons. In the nucleus, CAMAP acts as a transcriptional coactivator for CREB1 and is essential for the activation of ApC/EBP required for the initiation of LTF. Combined, our data suggest that CAMAP is a retrograde signaling component that translocates from activated synapses to the nucleus during synapse-specific LTF.
Asunto(s)
Aplysia/metabolismo , Moléculas de Adhesión Celular Neuronal/metabolismo , Núcleo Celular/metabolismo , Potenciación a Largo Plazo/fisiología , Sistema Nervioso/metabolismo , Neuronas Aferentes/metabolismo , Transporte Activo de Núcleo Celular/fisiología , Animales , Aplysia/citología , Moléculas de Adhesión Celular Neuronal/genética , Moléculas de Adhesión Celular Neuronal/aislamiento & purificación , Núcleo Celular/genética , Células Cultivadas , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Elementos de Facilitación Genéticos/fisiología , Humanos , Sistema Nervioso/citología , Serotonina/metabolismo , Transmisión Sináptica/fisiología , Activación Transcripcional/fisiologíaRESUMEN
Cellular and molecular studies of both implicit and explicit memory suggest that experience-dependent modulation of synaptic strength and structure is a fundamental mechanism by which these memories are encoded and stored within the brain. In this review, we focus on recent advances in our understanding of two types of memory storage: (i) sensitization in Aplysia, a simple form of implicit memory, and (ii) formation of explicit spatial memories in the mouse hippocampus. These two processes share common molecular mechanisms that have been highly conserved through evolution.
Asunto(s)
Memoria/fisiología , Animales , Aplysia , Conducta Animal , Encéfalo/citología , Encéfalo/fisiología , Humanos , Ratones , Modelos Neurológicos , Plasticidad Neuronal/fisiología , Sinapsis/fisiología , Factores de TranscripciónRESUMEN
Cellular studies of implicit and explicit memory suggest that experience-dependent modulation of synaptic strength and structure is a fundamental mechanism by which these memories are encoded, processed, and stored within the brain. In this review, we focus on recent advances in our understanding of the molecular mechanisms that underlie short-term, intermediate-term, and long-term forms of implicit memory in the marine invertebrate Aplysia californica, and consider how the conservation of common elements in each form may contribute to the different temporal phases of memory storage.
Asunto(s)
Aplysia/fisiología , Memoria/fisiología , Modelos Neurológicos , Animales , Aplysia/citología , Aplysia/metabolismo , Condicionamiento Clásico/fisiología , Memoria a Corto Plazo/fisiología , Reflejo/fisiología , Sinapsis/fisiologíaRESUMEN
Application of Clostridium difficile toxin B, an inhibitor of the Rho family of GTPases, at the Aplysia sensory to motor neuron synapse blocks long-term facilitation and the associated growth of new sensory neuron varicosities induced by repeated pulses of serotonin (5-HT). We have isolated cDNAs encoding Aplysia Rho, Rac, and Cdc42 and found that Rho and Rac had no effect but that overexpression in sensory neurons of a dominant-negative mutant of ApCdc42 or the CRIB domains of its downstream effectors PAK and N-WASP selectively reduces the long-term changes in synaptic strength and structure. FRET analysis indicates that 5-HT activates ApCdc42 in a subset of varicosities contacting the postsynaptic motor neuron and that this activation is dependent on the PI3K and PLC signaling pathways. The 5-HT-induced activation of ApCdc42 initiates reorganization of the presynaptic actin network leading to the outgrowth of filopodia, some of which are morphological precursors for the learning-related formation of new sensory neuron varicosities.
Asunto(s)
Actinas/metabolismo , Aprendizaje/fisiología , Plasticidad Neuronal/fisiología , Neuronas Aferentes/metabolismo , Serotonina/metabolismo , Sinapsis/metabolismo , Citoesqueleto de Actina/metabolismo , Actinas/efectos de los fármacos , Secuencia de Aminoácidos , Animales , Aplysia , Células Cultivadas , Secuencia Conservada/genética , Aprendizaje/efectos de los fármacos , Datos de Secuencia Molecular , Neuronas Motoras/citología , Neuronas Motoras/fisiología , Mutación/genética , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/aislamiento & purificación , Proteínas del Tejido Nervioso/metabolismo , Plasticidad Neuronal/efectos de los fármacos , Neuronas Aferentes/citología , Neuronas Aferentes/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Terminales Presinápticos/efectos de los fármacos , Terminales Presinápticos/metabolismo , Terminales Presinápticos/ultraestructura , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/aislamiento & purificación , Estructura Terciaria de Proteína/genética , Seudópodos/metabolismo , Serotonina/farmacología , Sinapsis/efectos de los fármacos , Fosfolipasas de Tipo C/metabolismo , Proteína Neuronal del Síndrome de Wiskott-Aldrich , Proteína de Unión al GTP cdc42/genética , Proteína de Unión al GTP cdc42/aislamiento & purificación , Proteína de Unión al GTP cdc42/metabolismo , Quinasas p21 Activadas , Proteínas de Unión al GTP rac/genética , Proteínas de Unión al GTP rac/aislamiento & purificación , Proteínas de Unión al GTP rac/metabolismo , Proteínas de Unión al GTP rho/genética , Proteínas de Unión al GTP rho/aislamiento & purificación , Proteínas de Unión al GTP rho/metabolismoRESUMEN
Recent cellular and molecular studies of both implicit and explicit memory storage suggest that experience-dependent modulation of synaptic strength and structure is a fundamental mechanism by which these diverse forms of memory are encoded and stored. For both forms of memory storage, some type of synaptic growth is thought to represent the stable cellular change that maintains the long-term process. In this review, we discuss recent findings on the molecular events that underlie learning-related synaptic growth in Aplysia and discuss the possibility that an active, prion-based mechanism is important for the maintenance of the structural change and for the persistence of long-term memory.
Asunto(s)
Memoria/fisiología , Modelos Biológicos , Sinapsis/fisiología , Animales , Humanos , Aprendizaje/fisiología , TiempoRESUMEN
The time course and functional significance of the structural changes associated with long-term facilitation of Aplysia sensory to motor neuron synaptic connections in culture were examined by time-lapse confocal imaging of individual sensory neuron varicosities labeled with three different fluorescent markers: the whole-cell marker Alexa-594 and two presynaptic marker proteins-synaptophysin-eGFP to monitor changes in synaptic vesicle distribution and synapto-PHluorin to monitor active transmitter release sites. Repeated pulses of serotonin induce two temporally, morphologically, and molecularly distinct presynaptic changes: (1) a rapid activation of silent presynaptic terminals by filling of preexisting empty varicosities with synaptic vesicles, which parallels intermediate-term facilitation, is completed within 3-6 hr and requires translation but not transcription and (2) a slower generation of new functional varicosities which occurs between 12-18 hr and requires transcription and translation. Enrichment of empty varicosities with synaptophysin accounts for 32% of the newly activated synapses at 24 hr, whereas newly formed varicosities account for 68%.