RESUMO
MicroRNAs (miRNAs) repress translation of target mRNAs by associating with Argonaute (Ago) proteins to form the RNA-induced silencing complex (RISC), underpinning a powerful mechanism for fine-tuning protein expression. Specific miRNAs are required for NMDA receptor (NMDAR)-dependent synaptic plasticity by modulating the translation of proteins involved in dendritic spine morphogenesis or synaptic transmission. However, it is unknown how NMDAR stimulation stimulates RISC activity to rapidly repress translation of synaptic proteins. We show that NMDAR stimulation transiently increases Akt-dependent phosphorylation of Ago2 at S387, which causes an increase in binding to GW182 and a rapid increase in translational repression of LIMK1 via miR-134. Furthermore, NMDAR-dependent down-regulation of endogenous LIMK1 translation in dendrites and dendritic spine shrinkage requires phospho-regulation of Ago2 at S387. AMPAR trafficking and hippocampal LTD do not involve S387 phosphorylation, defining this mechanism as a specific pathway for structural plasticity. This work defines a novel mechanism for the rapid transduction of NMDAR stimulation into miRNA-mediated translational repression to control dendritic spine morphology.
Assuntos
Proteínas Argonautas/genética , Quinases Lim/genética , MicroRNAs/genética , Receptores de N-Metil-D-Aspartato/genética , Animais , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/fisiologia , Hipocampo/metabolismo , Hipocampo/fisiologia , Humanos , Plasticidade Neuronal , Neurônios/metabolismo , Fosforilação , Ratos , Transdução de Sinais/genética , Transmissão Sináptica/genéticaRESUMO
Two forms of NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) at hippocampal CA1 synapses can be distinguished based on their sensitivity to inhibitors of protein kinase A (PKA). The PKA-dependent form requires multiple episodes of high-frequency stimulation (HFS) or theta burst stimuli (TBS) with a spacing between episodes in the order of minutes. To investigate the mechanism by which spaced episodes induce the PKA-dependent form of LTP, we have compared, in interleaved experiments, spaced (s) and compressed (c) TBS protocols in the rat CA1 synapses. We find that LTP induced by sTBS, but not that induced by cTBS, involves the insertion of calcium-permeable (CP) AMPARs, as assessed using pharmacological and electrophysiological criteria. Furthermore, a single TBS when paired with rolipram [4-(3-(cyclopentyloxy)-4-methoxyphenyl)pyrrolidin-2-one], to activate PKA, generates an LTP that also involves the insertion of CP-AMPARs. These data demonstrate that the involvement of CP-AMPARs in LTP is critically determined by the timing of the induction trigger and is associated specifically with the PKA-dependent form of LTP. SIGNIFICANCE STATEMENT: Long-term potentiation is a family of synaptic mechanisms that are believed to be important for learning and memory. Two of the most extensively studied forms are triggered by the synaptic activation of NMDA receptors and expressed by changes in AMPA receptor function. They can be distinguished on the basis of their requirement for activation of a protein kinase, PKA. We show that the PKA-dependent form also involves the transient insertion of calcium-permeable AMPA receptors. These results have implications for relating synaptic plasticity to learning and memory and suggest a specific linkage between PKA activation and the rapid synaptic insertion of calcium-permeable AMPA receptors during long-term potentiation.
Assuntos
Cálcio/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Potenciação de Longa Duração/fisiologia , Neurônios/fisiologia , Receptores de AMPA/metabolismo , Adamantano/análogos & derivados , Adamantano/farmacologia , Análise de Variância , Animais , Biofísica , Estimulação Elétrica , Inibidores Enzimáticos/farmacologia , Antagonistas de Aminoácidos Excitatórios , Hipocampo/citologia , Técnicas In Vitro , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Técnicas de Patch-Clamp , Poliaminas/farmacologia , Ratos , Receptores de AMPA/agonistas , Receptores de AMPA/antagonistas & inibidores , Rolipram/farmacologiaRESUMO
Group I metabotropic glutamate receptor (mGluR) dependent long-term depression (LTD) is a major form of synaptic plasticity underlying learning and memory. The molecular mechanisms involved in mGluR-LTD have been investigated intensively for the last two decades. In this 60th anniversary special issue article, we review the recent advances in determining the mechanisms that regulate the induction, transduction and expression of mGluR-LTD in the hippocampus, with a focus on the mitogen-activated protein kinase (MAPK) pathways. In particular we discuss the requirement of p38 MAPK and extracellular signal-regulated kinase 1/2 (ERK 1/2) activation. The recent advances in understanding the signaling cascades regulating mGluR-LTD are then related to the cognitive impairments observed in neurological disorders, such as fragile X syndrome and Alzheimer's disease. mGluR-LTD is a form of synaptic plasticity that impacts on memory formation. In the hippocampus mitogen-activated protein kinases (MAPKs) have been found to be important in mGluR-LTD. In this 60th anniversary special issue article, we review the independent and complementary roles of two classes of MAPK, p38 and ERK1/2 and link this to the aberrant mGluR-LTD that has an important role in diseases. This article is part of the 60th Anniversary special issue.
Assuntos
Hipocampo/enzimologia , Depressão Sináptica de Longo Prazo/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Doenças do Sistema Nervoso/enzimologia , Receptores de Glutamato Metabotrópico/fisiologia , Animais , Nível de Saúde , Hipocampo/patologia , Humanos , Doenças do Sistema Nervoso/patologiaRESUMO
The roles of Ca2+-induced calcium release in synaptic plasticity and metaplasticity are poorly understood. The present study has addressed the role of intracellular Ca2+ stores in long-term potentiation (LTP) and a form of heterosynaptic metaplasticity known as synaptic tagging and capture (STC) at CA1 synapses in mouse hippocampal slices. The effects of two compounds, ryanodine and cyclopiazonic acid (CPA), were examined on LTP induced by three distinct induction protocols: weak (w), compressed (c) and spaced (s) theta-burst stimulation (TBS). These compounds did not significantly affect LTP induced by the wTBS (one episode of TBS; 25 stimuli) or cTBS (three such episodes with a 10 s inter-episode interval (IEI); 75 stimuli) but substantially inhibited LTP induced by a sTBS (10 min IEI; 75 stimuli). Ryanodine and CPA also prevented a small heterosynaptic potentiation that was observed with the sTBS protocol. Interestingly, these compounds also prevented STC when present during either the sTBS or the subsequent wTBS, applied to an independent input. All of these effects of ryanodine and CPA were similar to that of a calcium-permeable AMPA receptor blocker. In conclusion, Ca2+ stores provide one way in which signals are propagated between synaptic inputs and, by virtue of their role in STC, may be involved in associative long-term memories. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
Assuntos
Cálcio , Potenciação de Longa Duração , Rianodina , Sinapses , Animais , Potenciação de Longa Duração/fisiologia , Camundongos , Sinapses/fisiologia , Rianodina/farmacologia , Cálcio/metabolismo , Indóis/farmacologia , Hipocampo/fisiologia , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/fisiologia , Região CA1 Hipocampal/fisiologia , MasculinoRESUMO
In area CA1 of the hippocampus, long-term depression (LTD) can be induced by activating group I metabotropic glutamate receptors (mGluRs), with the selective agonist DHPG. There is evidence that mGluR-LTD can be expressed by either a decrease in the probability of neurotransmitter release [P(r)] or by a change in postsynaptic AMPA receptor number. However, what determines the locus of expression is unknown. We investigated the expression mechanisms of mGluR-LTD using either a low (30 µM) or a high (100 µM) concentration of (RS)-DHPG. We found that 30 µM DHPG generated presynaptic LTD that required the co-activation of NMDA receptors, whereas 100 µM DHPG resulted in postsynaptic LTD that was independent of the activation of NMDA receptors. We found that both forms of LTD occur at the same synapses and that these may constitute the population with the lowest basal P(r). Our results reveal an unexpected complexity to mGluR-mediated synaptic plasticity in the hippocampus.
RESUMO
Astrocytes express a plethora of G protein-coupled receptors (GPCRs) that are crucial for shaping synaptic activity. Upon GPCR activation, astrocytes can respond with transient variations in intracellular Ca2+. In addition, Ca2+-dependent and/or Ca2+-independent release of gliotransmitters can occur, allowing them to engage in bidirectional neuron-astrocyte communication. The development of designer receptors exclusively activated by designer drugs (DREADDs) has facilitated many new discoveries on the roles of astrocytes in both physiological and pathological conditions. They are an excellent tool, as they can target endogenous GPCR-mediated intracellular signal transduction pathways specifically in astrocytes. With increasing interest and accumulating research on this topic, several discrepancies on astrocytic Ca2+ signalling and astrocyte-mediated effects on synaptic plasticity have emerged, preventing a clear-cut consensus about the downstream effects of DREADDs in astrocytes. In the present study, we performed a side-by-side evaluation of the effects of bath application of the DREADD agonist, clozapine-N-oxide (10 µM), on Gq- and Gi-DREADD activation in mouse CA1 hippocampal astrocytes. In doing so, we aimed to avoid confounding factors, such as differences in experimental procedures, and to directly compare the actions of both DREADDs on astrocytic intracellular Ca2+ dynamics and synaptic plasticity in acute hippocampal slices. We used an adeno-associated viral vector approach to transduce dorsal hippocampi of male, 8-week-old C57BL6/J mice, to drive expression of either the Gq-DREADD or Gi-DREADD in CA1 astrocytes. A viral vector lacking the DREADD construct was used to generate controls. Here, we show that agonism of Gq-DREADDs, but not Gi-DREADDs, induced consistent increases in spontaneous astrocytic Ca2+ events. Moreover, we demonstrate that both Gq-DREADD as well as Gi-DREADD-mediated activation of CA1 astrocytes induces long-lasting synaptic potentiation in the hippocampal CA1 Schaffer collateral pathway in the absence of a high frequency stimulus. Moreover, we report for the first time that astrocytic Gi-DREADD activation is sufficient to elicit de novo potentiation. Our data demonstrate that activation of either Gq or Gi pathways drives synaptic potentiation through Ca2+-dependent and Ca2+-independent mechanisms, respectively.
Assuntos
Astrócitos/fisiologia , Região CA1 Hipocampal/fisiologia , Sinalização do Cálcio/fisiologia , Clozapina/análogos & derivados , Drogas Desenhadas/farmacologia , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/fisiologia , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Animais , Astrócitos/efeitos dos fármacos , Região CA1 Hipocampal/citologia , Clozapina/farmacologia , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/efeitos dos fármacos , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/efeitos dos fármacos , Vetores Genéticos/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/fisiologia , Receptores Acoplados a Proteínas G/efeitos dos fármacosRESUMO
Glycogen synthase kinase 3 (GSK-3) is a Ser/Thr protein kinase that regulates many cellular processes, including synaptic plasticity. Previously, we reported that inhibition of GSK-3 prevents the induction of one of the major forms of synaptic plasticity, N-methyl-D-aspartate receptor (NMDAR)-dependent long-term depression (LTD), in hippocampal slices. In the present study, we have investigated the effects of inhibiting GSK-3 on learning and memory in healthy naïve animals. Systemic administration of a highly selective GSK-3 inhibitor, CT99021, reversibly blocked NMDAR-dependent LTD in the CA1 region of the hippocampus in anesthetized adult mice. In behavioral tasks, CT99021 had no effect on locomotor activity, anxiety, hippocampus-dependent contextual fear memory, and hippocampus-dependent reversal learning. However, CT99021 facilitated the rate of learning in the Morris water maze (MWM) and T-maze and enhanced the accuracy of long-term spatial memory in the MWM. These findings suggest that GSK-3 regulates the accuracy of spatial memory acquisition and recall.
RESUMO
Long-term potentiation (LTP) at hippocampal CA1 synapses can be expressed by an increase either in the number (N) of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors or in their single channel conductance (γ). Here, we have established how these distinct synaptic processes contribute to the expression of LTP in hippocampal slices obtained from young adult rodents. LTP induced by compressed theta burst stimulation (TBS), with a 10 s inter-episode interval, involves purely an increase in N (LTPN). In contrast, either a spaced TBS, with a 10 min inter-episode interval, or a single TBS, delivered when PKA is activated, results in LTP that is associated with a transient increase in γ (LTPγ), caused by the insertion of calcium-permeable (CP)-AMPA receptors. Activation of CaMKII is necessary and sufficient for LTPN whilst PKA is additionally required for LTPγ. Thus, two mechanistically distinct forms of LTP co-exist at these synapses.
Assuntos
Região CA1 Hipocampal/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Potenciais Pós-Sinápticos Excitadores/fisiologia , Potenciação de Longa Duração/fisiologia , Receptores de AMPA/metabolismo , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Masculino , Memória de Longo Prazo/fisiologia , Técnicas de Patch-Clamp , Ratos , Ritmo Teta/fisiologiaRESUMO
Excitatory synapses in the mammalian cortex are highly diverse, both in terms of their structure and function. However, relationships between synaptic features indicate they are highly coordinated entities. Imaging techniques, that enable physiology at the resolution of individual synapses to be investigated, have allowed the presynaptic activity level of the synapse to be related to postsynaptic function. This approach has revealed that neuronal activity induces the pre- and post-synapse to be functionally correlated and that subsets of synapses are more susceptible to certain forms of synaptic plasticity. As presynaptic function is often examined in isolation from postsynaptic properties, the effect it has on the post-synapse is not fully understood. However, since postsynaptic receptors at excitatory synapses respond to release of glutamate, it follows that they may be differentially regulated depending on the frequency of its release. Therefore, examining postsynaptic properties in the context of presynaptic function may be a useful way to approach a broad range of questions on synaptic physiology. In this review, we focus on how optophysiology tools have been utilized to study relationships between the pre- and the post-synapse. Multiple imaging techniques have revealed correlations in synaptic properties from the submicron to the dendritic level. Optical tools together with advanced imaging techniques are ideally suited to illuminate this area further, due to the spatial resolution and control they allow.
Assuntos
Encéfalo/metabolismo , Plasticidade Neuronal/fisiologia , Terminações Pré-Sinápticas/metabolismo , Sinapses/metabolismo , Potenciais Sinápticos/fisiologia , Animais , Encéfalo/ultraestrutura , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Humanos , Terminações Pré-Sinápticas/ultraestrutura , Receptores de AMPA/metabolismo , Sinapses/ultraestrutura , Transmissão Sináptica/fisiologiaRESUMO
Nam et al. (2019) genetically modulate the expression of astrocytic µ-opioid receptors to reveal they are necessary for drug-induced conditioned place preference. These receptors trigger a mechanism involving metabotropic glutamate receptors to enhance hippocampal long-term potentiation, linking the conditioning to the location.
Assuntos
Potenciação de Longa Duração , Receptores de Glutamato Metabotrópico , Hipocampo , Receptores Opioides , Lobo TemporalRESUMO
Classically, long-term potentiation (LTP) at hippocampal CA1 synapses is triggered by the synaptic activation of NMDA receptors (NMDARs). More recently, it has been shown that calcium-permeable (CP)-AMPARs can also trigger synaptic plasticity at these synapses. Specifically, their activation is required for the PKA and protein synthesis dependent component of LTP that is typically induced by delivery of spaced trains of high frequency stimulation. Here we present new data that build upon these ideas, including the requirement for low frequency synaptic activation and NMDAR dependence. We also show that a spaced theta burst stimulation (sTBS) protocol induces a heterosynaptic potentiation of baseline responses via activation of CP-AMPARs. Finally, we present data that implicate CP-AMPARs in synaptic tagging and capture, a fundamental process that is associated with the protein synthesis-dependent component of LTP. We have studied how a sTBS can augment the level of LTP generated by a weak TBS (wTBS), delivered 30 min later to an independent input. We show that inhibition of CP-AMPARs during the sTBS eliminates, and that inhibition of CP-AMPARs during the wTBS reduces, this facilitation of LTP. These data suggest that CP-AMPARs are crucial for the protein synthesis-dependent component of LTP and its heterosynaptic nature.
RESUMO
Theta-burst stimulation (TBS) induces short-term potentiation (STP) plus two types of transcriptionally-independent forms of long-term potentiation (LTP), termed LTP1 and LTP2. We have compared the susceptibility of these three types of synaptic plasticity to depotentiation, induced by low frequency stimulation (LFS; 2 Hz for 10 min) at the Schaffer collateral-commissural pathway in area CA1 of adult rat hippocampal slices. In interleaved experiments, STP and LTP were induced by three episodes of either compressed or spaced TBS (cTBS or sTBS). LFS had a more pronounced effect on the LTP induced by the cTBS. One traditional interpretation of these results is a difference in the time-dependent immunity against depotentiation. We suggest an alternative explanation: LFS rapidly reverses STP to reveal a slowly developing LTP. The cTBS protocol induces LTP1 that is moderately sensitive to depotentiation. The sTBS induces an additional component of LTP (LTP2) that is resistant to depotentiation.
Assuntos
Hipocampo/fisiologia , Potenciação de Longa Duração/fisiologia , Sinapses/fisiologia , Animais , Estimulação Elétrica , Depressão Sináptica de Longo Prazo/fisiologia , Masculino , Ratos Sprague-Dawley , Ritmo Teta/fisiologiaRESUMO
Long-term potentiation (LTP) at hippocampal CA1 synapses is classically triggered by the synaptic activation of NMDA receptors (NMDARs). More recently, it has been shown that calcium-permeable (CP) AMPA receptors (AMPARs) can also trigger synaptic plasticity at these synapses. Here, we review this literature with a focus on recent evidence that CP-AMPARs are critical for the induction of the protein kinase A (PKA)- and protein synthesis-dependent component of LTP.
RESUMO
A major mechanism contributing to synaptic plasticity involves alterations in the number of AMPA receptors (AMPARs) expressed at synapses. Hippocampal CA1 synapses, where this process has been most extensively studied, are highly heterogeneous with respect to their probability of neurotransmitter release, P(r). It is unknown whether there is any relationship between the extent of plasticity-related AMPAR trafficking and the initial P(r) of a synapse. To address this question, we induced metabotropic glutamate receptor (mGluR) dependent long-term depression (mGluR-LTD) and assessed AMPAR trafficking and P(r) at individual synapses, using SEP-GluA2 and FM4-64, respectively. We found that either pharmacological or synaptic activation of mGluR1 reduced synaptic SEP-GluA2 in a manner that depends upon P(r); this process involved an activity-dependent reduction in surface mGluR1 that selectively protects high-P(r) synapses from synaptic weakening. Consequently, the extent of postsynaptic plasticity can be pre-tuned by presynaptic activity.
Assuntos
Membrana Celular/metabolismo , Neurotransmissores/metabolismo , Receptores de AMPA/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/metabolismo , Endocitose/efeitos dos fármacos , Glutamatos/metabolismo , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Masculino , Metoxi-Hidroxifenilglicol/análogos & derivados , Metoxi-Hidroxifenilglicol/farmacologia , Probabilidade , Transporte Proteico/efeitos dos fármacos , Ratos Sprague-Dawley , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Ritmo Teta/efeitos dos fármacosRESUMO
Two forms of long-term depression (LTD), triggered by activation of NMDA receptors (NMDARs) and metabotropic glutamate receptors (mGluRs), respectively, can be induced at CA1 synapses in the hippocampus. Compared with NMDAR-LTD, relatively little is known about mGluR-LTD. Here, we show that protein tyrosine phosphatase (PTP) inhibitors, orthovanadate and phenylarsine oxide, selectively block mGluR-LTD induced by application of the group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG-LTD), because NMDAR-LTD is unaffected by these inhibitors. Furthermore, DHPG-LTD measured using whole-cell recording is similarly blocked by either bath-applied or patch-loaded PTP inhibitors. These inhibitors also block the changes in paired-pulse facilitation and coefficient of variation that are associated with the expression of DHPG-LTD. DHPG treatment of hippocampal slices was associated with a decrease in the level of tyrosine phosphorylation of GluR2 AMPA receptor (AMPAR) subunits, an effect blocked by orthovanadate. Finally, in dissociated hippocampal neurons, orthovanadate blocked the ability of DHPG to reduce the number of AMPA receptor clusters on the surface of dendrites. Again, the effects of PTP blockade were selective, because NMDA-induced decreases in surface AMPAR clusters was unaffected by orthovanadate. Together, these data suggest that activation of postsynaptic PTP results in tyrosine dephosphorylation of AMPARs and their removal from the synapse.
Assuntos
Depressão Sináptica de Longo Prazo/fisiologia , Neurônios/fisiologia , Proteínas Tirosina Fosfatases/fisiologia , Receptores de AMPA/metabolismo , Receptores de Glutamato Metabotrópico/fisiologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Análise de Variância , Animais , Animais Recém-Nascidos , Western Blotting/métodos , Células Cultivadas , Interações Medicamentosas , Estimulação Elétrica/métodos , Inibidores Enzimáticos/farmacologia , Feminino , Hipocampo/citologia , Imuno-Histoquímica/métodos , Imunoprecipitação/métodos , Técnicas In Vitro , Metoxi-Hidroxifenilglicol/análogos & derivados , Metoxi-Hidroxifenilglicol/farmacologia , N-Metilaspartato/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/efeitos da radiação , Técnicas de Patch-Clamp/métodos , Fosforilação , Transporte Proteico , Ratos , Ratos WistarRESUMO
N-methyl-d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) is extensively studied since it is believed to use the same molecular mechanisms that are required for many forms of learning and memory. Unfortunately, many controversies exist, not least the seemingly simple issue concerning the locus of expression of LTP. Here, we review our recent work and some of the extensive literature on this topic and present new data that collectively suggest that LTP can be explained, during its first few hours, by the coexistence of at least three mechanistically distinct processes that are all triggered by the synaptic activation of NMDARs.
Assuntos
Região CA1 Hipocampal/fisiologia , Potenciação de Longa Duração/fisiologia , Modelos Neurológicos , Plasticidade Neuronal/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/fisiologia , HumanosRESUMO
Phosphodiesterases (PDEs) degrade cyclic nucleotides, signalling molecules that play important roles in synaptic plasticity and memory. Inhibition of PDEs may therefore enhance synaptic plasticity and memory as a result of elevated levels of these signalling molecules, and this has led to interest in PDE inhibitors as cognitive enhancers. The development of new mouse models in which PDE subtypes have been selectively knocked out and increasing selectivity of PDE antagonists means that this field is currently expanding. Roles for PDE2, 4, 5 and 9 in synaptic plasticity have so far been demonstrated and we review these studies here in the context of cyclic nucleotide signalling more generally. The role of other PDE families in synaptic plasticity has not yet been investigated, and this area promises to advance our understanding of cyclic nucleotide signalling in synaptic plasticity in the future. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/fisiologia , Hipocampo/enzimologia , Hipocampo/fisiologia , Plasticidade Neuronal/fisiologia , Animais , AMP Cíclico/fisiologia , GMP Cíclico/fisiologia , Isoenzimas/fisiologia , Transdução de Sinais/fisiologiaRESUMO
Long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission are forms of synaptic plasticity that have been studied extensively and are thought to contribute to learning and memory. The reversal of LTP, known as depotentiation (DP) has received far less attention however, and its role in behavior is also far from clear. Recently, deficits in depotentiation have been observed in models of schizophrenia, suggesting that a greater understanding of this form of synaptic plasticity may help reveal the physiological alterations that underlie symptoms experienced by patients. This review therefore seeks to summarize the current state of knowledge on DP, and then put the deficits in DP in models of disease into this context.
RESUMO
The risk of developing schizophrenia has been linked to perturbations in embryonic development, but the physiological alterations that result from such insults are incompletely understood. Here, we have investigated aspects of hippocampal physiology in a proposed neurodevelopmental model of schizophrenia, induced during gestation in rats by injection of the antimitotic agent methylazoxymethanol acetate (MAM) at embryonic day 17 (MAM(E17)). We observed a reduction in synaptic innervation and synaptic transmission in the dorsal hippocampus of MAM(E17) treated rats, accompanied by a pronounced increase in CA1 pyramidal neuron excitability. Pharmacological investigations suggested that a deficit in GABAergic inhibition could account for the increase in excitability; furthermore, some aspects of the hyper-excitability could be normalised by the GABA(A) receptor (GABA(A)R) potentiator diazepam. Despite these alterations, two major forms of synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD) could be readily induced. In contrast, there was a substantial deficit in the reversal of LTP, depotentiation. These findings suggest that delivering neurodevelopmental insults at E17 may offer insights into some of the physiological alterations that underlie behavioural and cognitive symptoms observed in schizophrenia.
Assuntos
Modelos Animais de Doenças , Hipocampo/embriologia , Hipocampo/metabolismo , Plasticidade Neuronal , Esquizofrenia/metabolismo , Transmissão Sináptica , Animais , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Feminino , Hipocampo/efeitos dos fármacos , Masculino , Acetato de Metilazoximetanol/toxicidade , Plasticidade Neuronal/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Gravidez , Ratos , Ratos Sprague-Dawley , Esquizofrenia/induzido quimicamente , Transmissão Sináptica/efeitos dos fármacosRESUMO
Administration of the DNA-alkylating agent methylazoxymethanol acetate (MAM) on embryonic day 17 (E17) produces behavioral and anatomical brain abnormalities, which model some aspects of schizophrenia. This has lead to the premise that MAM rats are a neurodevelopmental model for schizophrenia. However, the underlying molecular pathways affected in this model have not been elucidated. In this study, we investigated the molecular phenotype of adult MAM rats by focusing on the frontal cortex and hippocampal areas, as these are known to be affected in schizophrenia. Proteomic and metabonomic analyses showed that the MAM treatment on E17 resulted primarily in deficits in hippocampal glutamatergic neurotransmission, as seen in some schizophrenia patients. Most importantly, these results were consistent with our finding of functional deficits in glutamatergic neurotransmission, as identified using electrophysiological recordings. Thus, this study provides the first molecular evidence, combined with functional validation, that the MAM-E17 rat model reproduces hippocampal deficits relevant to the pathology of schizophrenia.