RESUMO
Beta-adrenergic receptor (ß-AR) activation by norepinephrine (NE) enhances memory and stabilizes long-term potentiation (LTP), a form of synaptic plasticity believed to underlie some forms of hippocampal memory. LTP can occur at multiple synaptic pathways as a result of strong stimulation to one pathway preceding milder stimulation of an adjacent, independent pathway. Synaptic tagging allows LTP to be transferred, or captured, at heterosynaptic pathways. Previous research has shown that ß-AR activation promotes heterosynaptic LTP by engaging various signaling cascades. In particular, cyclic adenosine monophosphate (cAMP) activates cAMP-dependent protein kinase A (PKA) and guanine nucleotide exchange protein activated by cAMP (Epac), to enhance LTP. Epac activation can occlude subsequent induction of stable homosynaptic LTP after ß-AR activation, but it is unclear whether Epac activation is required for heterosynaptic LTP following pairing of the natural transmitter, NE, with one 100 Hz train of stimulation ("NE-LTP"). Using electrophysiologic recordings of CA1 field excitatory postsynaptic potentials during stimulation of two independent synaptic pathways in murine hippocampal slices, we show that distinct inhibitors of Epac blocked stabilization of homo- and heterosynaptic NE-LTP. PKA inhibition also attenuated heterosynaptic transfer of NE-LTP, but only when a PKA inhibitor was applied during tetanization of a second, heterosynaptic pathway that was not treated with NE. Our data suggest that NE, paired with 100 Hz, activates Epac to stabilize homo- and heterosynaptic LTP. Epac may regulate the production of plasticity-related proteins and subsequent synaptic capture of NE-LTP at a heterosynaptic pathway. Epac activation under these conditions may enable behavioral experiences that engage noradrenergic inputs to hippocampal circuits to be transformed into stable long-term memories.
Assuntos
Fatores de Troca do Nucleotídeo Guanina/metabolismo , Hipocampo/metabolismo , Potenciação de Longa Duração/fisiologia , Norepinefrina/metabolismo , Sinapses/metabolismo , Animais , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Estimulação Elétrica , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Receptores Adrenérgicos beta/metabolismo , Sinapses/efeitos dos fármacos , Técnicas de Cultura de TecidosRESUMO
Beta-adrenergic receptors (ß-ARs) prime hippocampal synapses to stabilize long-term potentiation (LTP). This "metaplasticity" can persist for 1-2 h after pharmacologic activation of ß-ARs. It requires activation of PKA (cAMP-dependent protein kinase) during ß-AR priming. A-kinase anchoring proteins (AKAPs) tether PKA to downstream signaling proteins. We hypothesized that induction of this metaplasticity requires intact functioning of AKAPs. Acute application of stearated ht31, a membrane-permeant inhibitor of AKAPs, either during ß-AR activation 30 min prior to LTP induction or during LTP induction, attenuated the persistence of LTP. A control, inactive ht31 peptide did not affect ß-AR-mediated metaplasticity. These findings implicate PKA anchoring in the induction of ß-adrenergic metaplasticity of LTP.
Assuntos
Proteínas de Ancoragem à Quinase A/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Hipocampo/fisiologia , Potenciação de Longa Duração/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Receptores Adrenérgicos beta/fisiologia , Animais , Potenciais Pós-Sinápticos Excitadores , Masculino , Camundongos Endogâmicos C57BL , Sinapses/fisiologiaRESUMO
Altered synaptic strength underlies information storage in neural circuits. Neuromodulatory transmitters such as norepinephrine (NE) facilitate long-lasting synaptic plasticity by recruiting and modifying multiple molecular elements of synaptic signaling, including specific transmitter receptors, intracellular protein kinases, and translation initiation. NE regulates multiple brain functions such as attention, perception, arousal, sleep, learning, and memory. The mammalian hippocampus receives noradrenergic innervation and hippocampal neurons express ß-adrenergic receptors (ß-ARs), which bind NE and are critical for gating the induction of long-lasting forms of synaptic potentiation. These forms of long-term potentiation (LTP) are believed to importantly contribute to long-term storage of spatial and contextual memories in neural circuits. In this article, in honor of Prof. Harold Atwood, we review the contributions of ß-ARs towards gating the expression of protein synthesis-dependent, long-lasting hippocampal LTP. We focus on the roles of ß-ARs in modifying ion channels, glutamatergic AMPA receptors, and translation initiation factors during LTP. We discuss prospective research strategies that may lead to increased understanding of the roles of NE in regulating neural circuit physiology; these may uncover novel therapies for treatment of specific neurological disorders linked to aberrant circuit activity and dysfunctional noradrenergic synaptic transmission.
Assuntos
Hipocampo/fisiologia , Potenciação de Longa Duração/fisiologia , Receptores Adrenérgicos beta/fisiologia , Animais , HumanosRESUMO
KEY POINTS: Transcription is recruited by noradrenaline in the hippocampus. Epigenetic mechanisms are recruited by hippocampal noradrenergic receptor activation. Epigenetic regulation by noradrenaline offers a novel mechanism for long-term potentiation ABSTRACT: Noradrenaline (NA) is a neuromodulator that can effect long-lasting changes in synaptic strength such as long-term potentiation (LTP), a putative cellular mechanism for memory formation in the mammalian brain. Persistent LTP requires alterations in gene expression that may involve epigenetic mechanisms such as DNA methylation, histone acetylation and histone phosphorylation. It is known that ß-adrenergic receptors and NA can boost LTP maintenance by regulating translation. However, it is unclear whether NA can additionally engage epigenetic mechanisms to regulate transcription and boost LTP endurance. To address this issue, we probed NA-treated mouse hippocampal slices with pharmacological inhibitors targeting epigenetic regulatory pathways and discovered that NA activates ß-adrenergic receptors to boost LTP maintenance in area CA1 through DNA methylation and post-translational histone modifications. Specifically, NA paired with 100 Hz stimulation enhanced histone H3 acetylation and phosphorylation, both of which were required for NA-induced boosting of LTP maintenance. Together, our findings identify NA as a neuromodulatory transmitter capable of triggering epigenetic, transcriptional control of genes required for establishing persistent LTP in the mouse hippocampus. These modifications may contribute to the stabilization of memory.
Assuntos
Região CA1 Hipocampal/metabolismo , Epigênese Genética , Potenciação de Longa Duração , Norepinefrina/metabolismo , Receptores Adrenérgicos beta/metabolismo , Acetilação , Animais , Região CA1 Hipocampal/fisiologia , Histonas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Processamento de Proteína Pós-Traducional , Receptores Adrenérgicos beta/genéticaRESUMO
Norepinephrine (NE) is a key modulator of synaptic plasticity in the hippocampus, a brain structure crucially involved in memory formation. NE boosts synaptic plasticity mostly through initiation of signaling cascades downstream from beta (ß)-adrenergic receptors (ß-ARs). Previous studies demonstrated that a ß-adrenergic receptor agonist, isoproterenol, can modify the threshold for long-term potentiation (LTP), a putative cellular mechanism for learning and memory, in a process known as "metaplasticity." Metaplasticity is the ability of synaptic plasticity to be modified by prior experience. We asked whether NE itself could engage metaplastic mechanisms in area CA1 of mouse hippocampal slices. Using extracellular field potential recording and stimulation, we show that application of NE (10 µM), which did not alter basal synaptic strength, enhances the future maintenance of LTP elicited by subthreshold, high-frequency stimulation (HFS: 1 × 100 Hz, 1 sec). HFS applied 30 min after NE washout induced long-lasting (>4 h) LTP, which was significantly extended in duration relative to HFS alone. This NE-induced metaplasticity required ß1-AR activation, as coapplication of the ß1-receptor antagonist CGP-20712A (1 µM) attenuated maintenance of LTP. We also found that NE-mediated metaplasticity was translation- and transcription-dependent. Polysomal profiles of CA1 revealed increased translation rates for specific mRNAs during NE-induced metaplasticity. Thus, activation of ß-ARs by NE primes synapses for future long-lasting plasticity on time scales extending beyond fast synaptic transmission; this may facilitate neural information processing and the subsequent formation of lasting memories.
Assuntos
Região CA1 Hipocampal/fisiologia , Potenciação de Longa Duração/efeitos dos fármacos , Norepinefrina/fisiologia , Receptores de AMPA/metabolismo , Receptores Adrenérgicos beta/fisiologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Imidazóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Norepinefrina/farmacologia , Subunidades Proteicas/metabolismo , RNA Mensageiro/metabolismoRESUMO
Encoding new information in the brain requires changes in synaptic strength. Neuromodulatory transmitters can facilitate synaptic plasticity by modifying the actions and expression of specific signaling cascades, transmitter receptors and their associated signaling complexes, genes, and effector proteins. One critical neuromodulator in the mammalian brain is norepinephrine (NE), which regulates multiple brain functions such as attention, perception, arousal, sleep, learning, and memory. The mammalian hippocampus receives noradrenergic innervation and hippocampal neurons express ß-adrenergic receptors, which are known to play important roles in gating the induction of long-lasting forms of synaptic potentiation. These forms of long-term potentiation (LTP) are believed to importantly contribute to long-term storage of spatial and contextual memories in the brain. In this review, we highlight the contributions of noradrenergic signaling in general and ß-adrenergic receptors in particular, toward modulating hippocampal LTP. We focus on the roles of NE and ß-adrenergic receptors in altering the efficacies of specific signaling molecules such as NMDA and AMPA receptors, protein phosphatases, and translation initiation factors. Also, the roles of ß-adrenergic receptors in regulating synaptic "tagging" and "capture" of LTP within synaptic networks of the hippocampus are reviewed. Understanding the molecular and cellular bases of noradrenergic signaling will enrich our grasp of how the brain makes new, enduring memories, and may shed light on credible strategies for improving mental health through treatment of specific disorders linked to perturbed memory processing and dysfunctional noradrenergic synaptic transmission.
Assuntos
Hipocampo/fisiologia , Potenciação de Longa Duração/fisiologia , Neurônios/fisiologia , Receptores Adrenérgicos beta/metabolismo , Animais , Humanos , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismoRESUMO
Encoding new information requires dynamic changes in synaptic strength. The brain can boost synaptic plasticity through the secretion of neuromodulatory substances, including acetylcholine and noradrenaline. Considerable effort has focused on elucidating how neuromodulatory substances alter synaptic properties. However, determination of the potential synergistic interactions between different neuromodulatory systems remains incomplete. Previous results indicate that coactivation of ß-adrenergic and cholinergic receptors facilitated the conversion of STP to LTP through an extracellular signal-regulated kinase (ERK)-dependent mechanism. ERK signaling has been linked to synaptically localized translation regulation. Thus, we hypothesized that costimulation of noradrenergic and cholinergic receptors could initiate the transformation of STP to LTP through up-regulation of protein synthesis. Our results indicate that a protocol which yields STP (5 Hz, 5 sec) when paired with coapplication of the ß-adrenergic agonist, isoproterenol (ISO), and the cholinergic agonist, carbachol (CCh), induces translation-dependent LTP in mouse CA1. This form of LTP requires both ß1-adrenergic and M1 muscarinic receptor activation, as blocking either receptor subtype prevented LTP induction. Blocking ERK, mTOR, or translation reduced the expression of LTP induced with ISO + CCh. Taken together, our data demonstrate that coactivation of ß-adrenergic and muscarinic receptors facilitates the conversion of STP to LTP through a mechanism requiring translation initiation.
Assuntos
Região CA1 Hipocampal/fisiologia , Potenciação de Longa Duração/fisiologia , Receptores Adrenérgicos beta/fisiologia , Receptores Muscarínicos/fisiologia , Transdução de Sinais/fisiologia , Animais , Potenciais Pós-Sinápticos Excitadores/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Patch-Clamp , Biossíntese de ProteínasRESUMO
Silencing of a single gene, FMR1, is linked to a highly prevalent form of mental retardation, characterized by social and cognitive impairments, known as fragile X syndrome (FXS). The FMR1 gene encodes fragile X mental retardation protein (FMRP), which negatively regulates translation. Knockout of Fmr1 in mice results in enhanced long-term depression (LTD) induced by metabotropic glutamate receptor (mGluR) activation. Despite the evidence implicating FMRP in LTD, the role of FMRP in long-term potentiation (LTP) is less clear. Synaptic strength can be augmented heterosynaptically through the generation and sequestration of plasticity-related proteins, in a cell-wide manner. If heterosynaptic plasticity is altered in Fmr1 knockout (KO) mice, this may explain the cognitive deficits associated with FXS. We induced homosynaptic plasticity using the ß-adrenergic receptor (ß-AR) agonist, isoproterenol (ISO), which facilitated heterosynaptic LTP that was enhanced in Fmr1 KO mice relative to wild-type (WT) controls. To determine if enhanced heterosynaptic LTP in Fmr1 KO mouse hippocampus requires protein synthesis, we applied a translation inhibitor, emetine (EME). EME blocked homo- and heterosynaptic LTP in both genotypes. We also probed the roles of mTOR and ERK in boosting heterosynaptic LTP in Fmr1 KO mice. Although heterosynaptic LTP was blocked in both WT and KOs by inhibitors of mTOR and ERK, homosynaptic LTP was still enhanced following mTOR inhibition in slices from Fmr1 KO mice. Because mTOR will normally stimulate translation initiation, our results suggest that ß-AR stimulation paired with derepression of translation results in enhanced heterosynaptic plasticity.
Assuntos
Potenciais Pós-Sinápticos Excitadores/genética , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Hipocampo/citologia , Plasticidade Neuronal/genética , Neurônios/fisiologia , Agonistas Adrenérgicos beta/farmacologia , Animais , Bicuculina/farmacologia , Biofísica , Relação Dose-Resposta a Droga , Estimulação Elétrica/métodos , Emetina/farmacologia , Inibidores Enzimáticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Flavonoides/farmacologia , Proteína do X Frágil da Deficiência Intelectual/genética , Antagonistas de Receptores de GABA-A/farmacologia , Hipocampo/fisiologia , Imunossupressores/farmacologia , Técnicas In Vitro , Isoproterenol/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasticidade Neuronal/efeitos dos fármacos , Técnicas de Patch-Clamp , Piridinas/farmacologia , Sirolimo/farmacologia , Fatores de Tempo , Proteínas rap de Ligação ao GTP/farmacologiaRESUMO
Noradrenaline critically modulates the ability of synapses to undergo long-term plasticity on time scales extending well beyond fast synaptic transmission. Noradrenergic signalling through ß-adrenergic receptors (ß-ARs) enhances memory consolidation and can boost the longevity of long-term potentiation (LTP). Previous research has shown that stimulation of one synaptic pathway with a protocol that induces persistent, translation-dependent LTP can enable the induction of LTP by subthreshold stimulation at a second, independent synaptic pathway. This heterosynaptic facilitation depends on the regulation and synthesis of proteins. Recordings taken from area CA1 in mouse hippocampal slices showed that induction of ß-AR-dependent LTP at one synaptic pathway (S1) can facilitate LTP at a second, independent pathway (S2) when low-frequency, subthreshold stimulation is applied after a 30 min delay. ß-AR-dependent heterosynaptic facilitation requires protein synthesis as inhibition of mammalian target of rapamycin (mTOR), extracellular signal-regulated kinase (ERK), or translation, prevented homo- and heterosynaptic LTP. Shifting application of a translational repressor, emetine, to coincide with S2 stimulation did not block LTP. Heterosynaptic LTP was prevented in the presence of the cell-permeable cAMP-dependent protein kinase inhibitor, PKI. Conversely, the time window for inter-pathway transfer of heterosynaptic LTP was extended through inhibition of GluR2 endocytosis. Our data show that activation of ß-ARs boosts the heterosynaptic expression of translation-dependent LTP. These results suggest that engagement of the noradrenergic system may extend the associative capacity of hippocampal synapses through facilitation of intersynaptic crosstalk.
Assuntos
Potenciação de Longa Duração , Receptores Adrenérgicos beta , Animais , Estimulação Elétrica , Hipocampo , Camundongos Endogâmicos C57BLRESUMO
The capacity for long-term changes in synaptic efficacy can be altered by prior synaptic activity, a process known as "metaplasticity." Activation of receptors for modulatory neurotransmitters can trigger downstream signaling cascades that persist beyond initial receptor activation and may thus have metaplastic effects. Because activation of ß-adrenergic receptors (ß-ARs) strongly enhances the induction of long-term potentiation (LTP) in the hippocampal CA1 region, we examined whether activation of these receptors also had metaplastic effects on LTP induction. Our results show that activation of ß-ARs induces a protein synthesis-dependent form of metaplasticity that primes the future induction of late-phase LTP by a subthreshold stimulus. ß-AR activation also induced a long-lasting increase in phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) GluA1 subunits at a protein kinase A (PKA) site (S845) and transiently activated extracellular signal-regulated kinase (ERK). Consistent with this, inhibitors of PKA and ERK blocked the metaplastic effects of ß-AR activation. ß-AR activation also induced a prolonged, translation-dependent increase in cell surface levels of GluA1 subunit-containing AMPA receptors. Our results indicate that ß-ARs can modulate hippocampal synaptic plasticity by priming synapses for the future induction of late-phase LTP through up-regulation of translational processes, one consequence of which is the trafficking of AMPARs to the cell surface.
Assuntos
Potenciais Pós-Sinápticos Excitadores/fisiologia , Potenciação de Longa Duração/fisiologia , Receptores de AMPA/metabolismo , Receptores Adrenérgicos beta/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Biofísica , Carbazóis/farmacologia , Estimulação Elétrica/métodos , Inibidores Enzimáticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Técnicas In Vitro , Isoproterenol/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Patch-Clamp/métodos , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Propranolol/farmacologia , Pirróis/farmacologia , Serina/metabolismoRESUMO
Activation of beta-adrenergic receptors (beta-ARs) enhances hippocampal memory consolidation and long-term potentiation (LTP), a likely mechanism for memory storage. One signaling pathway linked to beta-AR activation is the cAMP-PKA pathway. PKA is critical for the consolidation of hippocampal long-term memory and for the expression of some forms of long-lasting hippocampal LTP. How does beta-AR activation affect the PKA-dependence, and persistence, of LTP elicited by distinct stimulation frequencies? Here, we use in vitro electrophysiology to show that patterns of stimulation determine the temporal phase of LTP affected by beta-AR activation. In addition, only specific patterns of stimulation recruit PKA-dependent LTP following beta-AR activation. Impairments of PKA-dependent LTP maintenance generated by pharmacologic or genetic deficiency of PKA activity are also abolished by concurrent activation of beta-ARs. Taken together, our data show that, depending on patterns of synaptic stimulation, activation of beta-ARs can gate the PKA-dependence and persistence of synaptic plasticity. We suggest that this may allow neuromodulatory receptors to fine-tune neural information processing to meet the demands imposed by numerous synaptic activity profiles. This is a form of "metaplasticity" that could control the efficacy of consolidation of hippocampal long-term memories.
Assuntos
Hipocampo/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Receptores Adrenérgicos beta/efeitos dos fármacos , Agonistas Adrenérgicos beta/administração & dosagem , Agonistas Adrenérgicos beta/farmacologia , Animais , Carbazóis/administração & dosagem , Carbazóis/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Estimulação Elétrica , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Feminino , Hipocampo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/administração & dosagem , Isoproterenol/administração & dosagem , Isoproterenol/farmacologia , Locus Cerúleo/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Camundongos Transgênicos , Rede Nervosa/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Pirróis/administração & dosagem , Pirróis/farmacologia , Proteínas RGS/efeitos dos fármacos , Receptores Adrenérgicos beta/metabolismo , Transmissão Sináptica/efeitos dos fármacosRESUMO
cAMP is a critical second messenger implicated in synaptic plasticity and memory in the mammalian brain. Substantial evidence links increases in intracellular cAMP to activation of cAMP-dependent protein kinase (PKA) and subsequent phosphorylation of downstream effectors (transcription factors, receptors, protein kinases) necessary for long-term potentiation (LTP) of synaptic strength. However, cAMP may also initiate signaling via a guanine nucleotide exchange protein directly activated by cAMP (Epac). The role of Epac in hippocampal synaptic plasticity is unknown. We found that in area CA1 of mouse hippocampal slices, activation of Epac enhances maintenance of LTP without affecting basal synaptic transmission. The persistence of this form of LTP requires extracellular signal-regulated protein kinase (ERK) and new protein synthesis, but not transcription. Because ERK is involved in translational control of long-lasting plasticity and memory, our data suggest that Epac is a crucial link between cAMP and ERK during some forms of protein synthesis-dependent LTP. Activation of Epac represents a novel signaling pathway for rapid regulation of the stability of enduring forms of LTP and, perhaps, of hippocampus- dependent long-term memories.
Assuntos
Fatores de Troca do Nucleotídeo Guanina/fisiologia , Hipocampo/fisiologia , Potenciação de Longa Duração/fisiologia , Animais , Butadienos/farmacologia , Carbazóis/farmacologia , AMP Cíclico/análogos & derivados , AMP Cíclico/farmacologia , AMP Cíclico/fisiologia , Dactinomicina/farmacologia , Emetina/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Feminino , Fatores de Troca do Nucleotídeo Guanina/agonistas , Isoproterenol/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Nitrilas/farmacologia , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Pirróis/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacosRESUMO
Neuromodulation regulates critical functions of CNS synapses, ranging from neural circuit development to high-order cognitive processes, including learning and memory. This broad scope of action is generally mediated through alterations of the strength of synaptic transmission (i.e. synaptic plasticity). Changes in synaptic strength are widely considered to be a cellular representation of learned information. Noradrenaline is a neuromodulator that is secreted throughout the brain in response to novelty or increased arousal. Once released, noradrenaline activates metabotropic receptors, initiating intracellular signaling cascades that promote enduring changes in synaptic strength and facilitate memory storage. Here, we provide an overview of noradrenergic modulation of synaptic plasticity and memory formation within mammalian neural circuits, which has broad applicability within the neurotherapeutics community. Advances in our understanding of noradrenaline in the context of these processes may provide a foundation for refining treatment strategies for multiple brain diseases, ranging from post-traumatic stress disorder to Alzheimer's Disease.
Assuntos
Neurônios Adrenérgicos/metabolismo , Hipocampo/metabolismo , Memória/fisiologia , Plasticidade Neuronal/fisiologia , Norepinefrina/metabolismo , Neurônios Adrenérgicos/patologia , Animais , Hipocampo/patologia , HumanosRESUMO
Studies of hippocampal long-term potentiation (LTP), a cellular model of memory storage, implicate cAMP-dependent protein kinase (PKA) in presynaptic and postsynaptic mechanisms of LTP. The anchoring of PKA to AKAPs (A kinase-anchoring proteins) creates compartmentalized pools of PKA, but the roles of presynaptically and postsynaptically anchored forms of PKA in late-phase LTP are unclear. In this study, we have created genetically modified mice that conditionally express Ht31, an inhibitor of PKA anchoring, to probe the roles of anchored PKA in hippocampal LTP and spatial memory. Our findings show that at hippocampal Schaffer collateral CA3-CA1 synapses, theta-burst LTP requires presynaptically anchored PKA. In addition, a pool of anchored PKA in hippocampal area CA3 is required for spatial memory. These findings reveal a novel and significant role for anchored PKA signaling in cellular mechanisms underlying memory storage.
Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Potenciação de Longa Duração/fisiologia , Aprendizagem em Labirinto/fisiologia , Transdução de Sinais/fisiologia , Sequência de Aminoácidos , Animais , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Dados de Sequência Molecular , Comportamento Espacial/fisiologia , Sinapses/enzimologia , Sinapses/genéticaRESUMO
The hippocampus is crucial for the consolidation of new declarative long-term memories. Genetic and behavioral experimentation have revealed that several protein kinases are critical for the formation of hippocampus-dependent long-term memories. Cyclic-AMP dependent protein kinase (PKA) is a serine-threonine kinase that has been strongly implicated in the expression of specific forms of hippocampus-dependent memory. We review evidence that PKA is required for hippocampus-dependent memory in mammals, and we highlight some of the proteins that have been implicated as targets of PKA. Future directions and open questions regarding the role of PKA in memory storage are also described.
Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Hipocampo/fisiologia , Memória/fisiologia , Animais , Potenciação de Longa Duração/fisiologia , Sinapses/fisiologiaRESUMO
The hippocampus is critical for memory formation. However, the contributions of the hippocampal commissure (HC) and the corpus callosum (CC) are less clear. To elucidate the role of the forebrain commissures in learning and memory, we performed a behavioural and electrophysiological characterization of an inbred mouse strain that displays agenesis of the CC and congenitally reduced HC (BTBR T+ tf/J; 'BTBR'). Compared to a control strain, BTBR mice have severely impaired contextual fear memory, with normal object recognition memory. Interestingly, continuous environmental "enrichment" significantly increased object recognition in BTBR, but not in control C57BL/6 ('BL/6') mice. In area CA1 of hippocampal slices, BTBR displayed intact expression of long-term potentiation (LTP), paired-pulse facilitation (PPF) and basal synaptic transmission, compared to BL/6 mice. However, BTBR hippocampal slices show an increased susceptibility to depotentiation (DPT), an activity-induced reversal of LTP. We conclude that the HC and CC are critical for some forms of hippocampal memory and for synaptic resistance to DPT. Agenesis of the CC and HC may unmask some latent ability to encode, store or retrieve certain forms of recognition memory. We suggest that the increased susceptibility to DPT in BTBR may underlie the memory phenotype reported here.
Assuntos
Corpo Caloso/fisiologia , Medo/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Plasticidade Neuronal/fisiologia , Agenesia do Corpo Caloso , Animais , Aprendizagem da Esquiva/fisiologia , Estimulação Elétrica , Feminino , Potenciação de Longa Duração/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes Neurológicos , Malformações do Sistema Nervoso/fisiopatologia , Vias Neurais/anormalidades , Vias Neurais/fisiologia , Técnicas de Cultura de Órgãos , Reconhecimento Visual de Modelos/fisiologia , Transmissão Sináptica/fisiologiaRESUMO
Long-term potentiation (LTP) is activity-dependent enhancement of synaptic strength that can critically regulate long-term memory storage. Like memory, LTP exhibits at least two mechanistically distinct temporal phases. Early LTP (E-LTP) does not require protein synthesis, whereas the late phase of LTP (L-LTP), like long-term memory, requires protein synthesis. Hippocampal beta-adrenergic receptors can regulate expression of both E-LTP and long-term memory. Although beta-adrenergic receptor activation enhances the ability of subthreshold stimuli to induce E-LTP, it is unclear whether such activation can facilitate induction of L-LTP. Here, we use electrophysiological recording methods on mouse hippocampal slices to show that when synaptic stimulation that is subthreshold for inducing L-LTP is paired with beta-adrenergic receptor activation, the resulting LTP persists for over 6 h in area CA1. Like L-LTP induced by multiple trains of high-frequency electrical stimulation, this LTP requires protein synthesis. Unlike tetanus-induced L-LTP, however, L-LTP induced by beta-adrenergic receptor activation during subthreshold stimulation appears to involve dendritic protein synthesis but not somatic transcription. Maintenance of this LTP also requires activation of extracellular signal-regulated kinases (ERKs). Thus, beta-adrenergic receptor activation elicits a type of L-LTP that requires translation and ERK activation but not transcription. This form of L-LTP may be a cellular mechanism for facilitation of behavioral long-term memory during periods of heightened emotional arousal that engage the noradrenergic modulatory system.
Assuntos
Dactinomicina/farmacologia , Potenciação de Longa Duração/fisiologia , Neurônios/fisiologia , Receptores Adrenérgicos beta/fisiologia , Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Anisomicina/farmacologia , Relação Dose-Resposta à Radiação , Interações Medicamentosas , Estimulação Elétrica/métodos , Inibidores Enzimáticos/farmacologia , Flavonoides/farmacologia , Hipocampo/citologia , Técnicas In Vitro , Isoproterenol/análogos & derivados , Isoproterenol/farmacologia , Potenciação de Longa Duração/efeitos da radiação , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/efeitos da radiação , Propranolol/farmacologia , Inibidores da Síntese de Proteínas/farmacologiaRESUMO
Long-term potentiation (LTP) is an enhancement of synaptic strength that may contribute to information storage in the mammalian brain. LTP expression can be regulated by previous synaptic activity, a process known as "metaplasticity." Cell-wide occurrence of metaplasticity may regulate synaptic strength. However, few reports have demonstrated metaplasticity at synapses that are silent during activity at converging synaptic inputs. We describe a novel form of cell-wide metaplasticity in hippocampal area CA1. Low-frequency stimulation (LFS) decreased the stability of long-lasting LTP ["late" LTP (L-LTP)] induced later at the same inputs (homosynaptic inhibition) and at other inputs converging on the same postsynaptic cells (heterosynaptic inhibition). Significantly, heterosynaptic inhibition of L-LTP also occurred across basal and apical dendrites ("heterodendritic" inhibition). Because transient early LTP (E-LTP) was not affected by previous LFS, we examined the effects of LFS on the consolidation of E-LTP to L-LTP. The duration of E-LTP induced at one set of inputs can be extended by capturing L-LTP-associated gene products generated by previous activity at other inputs to the same postsynaptic neurons. LFS applied homosynaptically or heterosynaptically before L-LTP induction did not impair synaptic capture by subsequent E-LTP stimulation, suggesting that LFS does not impair L-LTP-associated transcription. In contrast, LFS applied just before E-LTP (homosynaptically or heterosynaptically) prevented synaptic tagging, and capture of L-LTP expression. Thus, LFS inhibits synaptic tagging to impair expression of subsequent L-LTP. Such anterograde inhibition represents a novel way in which synaptic activity can regulate the expression of future long-lasting synaptic plasticity in a cell-wide manner.
Assuntos
Hipocampo/fisiologia , Potenciação de Longa Duração/fisiologia , Inibição Neural/fisiologia , Plasticidade Neuronal/fisiologia , Sinapses/fisiologia , Animais , Dendritos/metabolismo , Estimulação Elétrica/métodos , Potenciais Pós-Sinápticos Excitadores , Feminino , Expressão Gênica , Técnicas In Vitro , Depressão Sináptica de Longo Prazo/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/biossíntese , Fatores de Tempo , Transcrição Gênica/fisiologiaRESUMO
Understanding basic neuronal mechanisms hold the hope for future treatment of brain disease. The 1st international conference on synapse, memory, drug addiction and pain was held in beautiful downtown Toronto, Canada on August 21-23, 2006. Unlike other traditional conferences, this new meeting focused on three major aims: (1) to promote new and cutting edge research in neuroscience; (2) to encourage international information exchange and scientific collaborations; and (3) to provide a platform for active scientists to discuss new findings. Up to 64 investigators presented their recent discoveries, from basic synaptic mechanisms to genes related to human brain disease. This meeting was in part sponsored by Molecular Pain, together with University of Toronto (Faculty of Medicine, Department of Physiology as well as Center for the Study of Pain). Our goal for this meeting is to promote future active scientific collaborations and improve human health through fundamental basic neuroscience researches. The second international meeting on Neurons and Brain Disease will be held in Toronto (August 29-31, 2007).
Assuntos
Comportamento , Encefalopatias/patologia , Neurociências , Sinapses/fisiologia , HumanosRESUMO
De novo protein synthesis and transcription are necessary for the expression of long-lasting synaptic potentiation [long-term potentiation (LTP)] in hippocampal area CA1 and for the consolidation of long-term memory. The stability of LTP and its longevity require macromolecular synthesis at later stages, but a specific role for early protein synthesis has not been identified. Using electrophysiological recording methods in mouse hippocampal slices, we show that multiple trains of high-frequency stimulation provide immediate synaptic immunity to depotentiation. This immunity to depotentiation is dependent on the amount of synaptic stimulation used to induce LTP, it is input specific, and it is prevented by inhibitors of protein synthesis. We propose that local translation mediates input-specific synaptic immunity against depotentiation. We also present evidence suggesting that, in addition to translation, products of transcription can provide cell-wide immunity to depotentiation via heterosynaptic transfer of synaptic immunity between distinct pathways in area CA1. Protein synthesis and transcription may importantly regulate long-term storage of information by conferring synaptic immunity to depotentiation at previously potentiated synapses.