RESUMO
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
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
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
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
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
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
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
Beta-adrenergic receptors (beta-ARs) critically modulate long-lasting synaptic plasticity and long-term memory storage in the mammalian brain. Synaptic plasticity is widely believed to mediate memory storage at the cellular level. Long-term potentiation (LTP) is one type of synaptic plasticity that has been linked to memory storage. Activation of beta-ARs can enhance LTP and facilitate long-term memory storage. Interestingly, many of the molecular signaling pathways that are critical for beta-adrenergic modulation of LTP mirror those required for the persistence of memory. In this article, we review the roles of signaling cascades and translation regulation in enabling beta-ARs to control expression of long-lasting LTP in the rodent hippocampus. These include the cyclic-AMP/protein kinase-A (cAMP-PKA) and extracellular signal-regulated protein kinase cascades, two key pathways known to link transmitter receptors with translation regulation. Future research directions are discussed, with emphasis on defining the roles of signaling complexes (e.g. PSD-95) and glutamatergic receptors in controlling the efficacy of beta-AR modulation of LTP.
Assuntos
Hipocampo/fisiologia , Potenciação de Longa Duração/efeitos dos fármacos , Piperazinas/farmacologia , Receptores Adrenérgicos beta/metabolismo , Sulfonas/farmacologia , Sinapses/efeitos dos fármacos , Animais , Hipocampo/efeitos dos fármacos , Humanos , Purinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Citrato de SildenafilaRESUMO
Vietnamese adult and adolescent immigrants in the United States acculturate to the Western culture at different rates. MostVietnamese parents tend to use the authoritarian parenting method in which dictatorial approaches are enforced, possibly leading to family conflicts and mental health issues. By means of the Suinn-Lew Asian Self-Identity Acculturation Scale, the Parental Authority Questionnaire, the Rosenberg Self-Esteem Scale, and the Reynolds Adolescent Depression Inventory, this exploratory study surveyed 290Vietnamese American adolescents in a major metropolitan area to examine the relationship between their fathers' acculturation levels and parenting styles and the relationships among parenting styles and self-esteem levels and depression scores of the adolescents. Findings revealed that most of the adolescents perceived that their fathers have not acculturated to the U.S. culture and continue to practice the traditional authoritarian parenting style, regardless of the amount of time spent in the United States. Furthermore, results indicate that adolescents who perceived their fathers as using the authoritarian parenting style reported lower levels of self-esteem and higher depression scores when compared with those who perceived their fathers as using the authoritative parenting style.
Assuntos
Aculturação , Emigrantes e Imigrantes/psicologia , Relações Pai-Filho , Pai/psicologia , Transtornos Mentais/etnologia , Transtornos Mentais/terapia , Poder Familiar , Adolescente , Criança , Feminino , Humanos , Masculino , Autoimagem , Inquéritos e Questionários , Resultado do Tratamento , Estados Unidos , Vietnã/etnologiaRESUMO
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
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
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
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
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
beta-Adrenergic receptors critically modulate long-lasting synaptic plasticity and long-term memory in the mammalian hippocampus. Persistent long-term potentiation of synaptic strength requires protein synthesis and has been correlated with some forms of hippocampal long-term memory. However, the intracellular processes that initiate protein synthesis downstream of the beta-adrenergic receptor are unidentified. Here we report that activation of beta-adrenergic receptors recruits ERK and mammalian target of rapamycin signaling to facilitate long-term potentiation maintenance at the level of translation initiation. Treatment of mouse hippocampal slices with a beta-adrenergic receptor agonist results in activation of eukaryotic initiation factor 4E and the eukaryotic initiation factor 4E kinase Mnk1, along with inhibition of the translation repressor 4E-BP. This coordinated activation of translation machinery requires concomitant ERK and mammalian target of rapamycin signaling. Taken together, our data identify distinct signaling pathways that converge to regulate beta-adrenergic receptor-dependent protein synthesis during long-term synaptic potentiation in the hippocampus. We suggest that beta-adrenergic receptors play a crucial role in gating the induction of long-lasting synaptic plasticity at the level of translation initiation, a mechanism that may underlie the ability of these receptors to influence the formation of long-lasting memories.
Assuntos
MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Potenciação de Longa Duração , Biossíntese de Proteínas , Proteínas Quinases/fisiologia , Receptores Adrenérgicos beta/fisiologia , Transdução de Sinais , Animais , Fator de Iniciação 4E em Eucariotos/metabolismo , Fatores de Iniciação em Eucariotos/fisiologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Serina-Treonina Quinases TORRESUMO
Long-term potentiation (LTP), an activity-dependent enhancement of synaptic strength, and memory can be influenced by neuromodulatory transmitters such as norepinephrine (NE) and also by genetic background. beta-Adrenergic receptor activation can facilitate the expression of hippocampal CA1 LTP induced by weak stimulus patterns, but its influence on LTP induced by stronger stimulus patterns is unclear. We examined neural NE and dopamine (DA) levels, beta-adrenergic receptor expression and hippocampal LTP in genetically diverse inbred mouse strains. Brain tissue levels of NE were significantly lower in strains 129S1/SvImJ (129), BALB/cByJ (BALB) and C3H/HeJ (C3H) than in C57BL/6NCrlBR (B6). Western blot analysis showed that hippocampal beta(1)-adrenergic receptor expression was similar in strains B6, 129 and C3H, but was increased in BALB. LTP was induced in area CA1 of hippocampal slices by four trains of high-frequency stimulation (HFS) of the Schaeffer collaterals in the four inbred strains. Two hours after induction, LTP was significantly reduced in strains 129, BALB and C3H compared to B6, correlating with neural NE levels. We rescued hippocampal LTP in strains 129, BALB and C3H to levels seen in B6 by bath application of 1 microm isoproterenol, a beta-adrenergic receptor agonist, during HFS. Propranolol, a beta-adrenergic receptor antagonist, blocked this rescue in 129, BALB and C3H but did not affect LTP in strain B6. Thus, although this form of multitrain LTP does not rely on beta-adrenergic receptor activation, our data show that pharmacological activation of beta-adrenergic receptors during multiple trains of HFS can rescue CA1 LTP in genetically diverse strains with impaired LTP.