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Neurosilence: intracerebral applications of protein synthesis inhibitors eliminate neural activitySharma, Arjun V Unknown Date
No description available.
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Neurosilence: intracerebral applications of protein synthesis inhibitors eliminate neural activitySharma, Arjun V 11 1900 (has links)
The acquisition of a behavioural response (learning) and the later retrieval of this response (memory) are separated by an endogenous biological process which consolidates the temporary neural changes initiated by training. Intracerebral infusions of stimulants to the hippocampus potentiate this process and infusions of protein synthesis inhibitors (PSIs) impair it. A tacit assumption regarding the application of PSIs is that they have no effect upon spontaneous brain electrical activity; however, given their documented non-specific side effects, this idea was re-evaluated under controlled conditions. Hippocampal recordings were made in urethane anaesthetized rats before and after unilateral hippocampal infusions of the PSIs anisomycin and cycloheximide. Infusions suppressed local field potentials, eliminated sink/source alternations and silenced multiunit activity without affecting the contralateral hippocampus. This suppression was correlated with the degree of protein synthesis inhibition. These results present a serious confound for all results obtained using anisomycin and cycloheximide to test memory consolidation.
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Application of an affinity chromatography toolbox to drug repurposing for cancer therapeuticsCruickshank, Faye Louise January 2016 (has links)
Phenotypic screening of drug molecules relies on the generation of a specific response; however the means by which this is elicited often remains unknown. Affinity chromatography is a valuable tool in the discovery of drug binding partners and may even allow the elucidation of the wider interactome of the initial drug target. The introduction of easily cleavable linkers and affinity-independent elution protocols to affinity chromatography is of current interest, since they render the technique much more adaptable with respect to the characterisation of biologically active species of interest. This thesis details the application of a novel azobenzene linker developed by the Hulme group for use in affinity-independent chromatography. The first chapter reviews recent developments in affinity chromatography and describes the synthesis of an affinity linker toolbox with both affinity-dependent and affinity-independent linkers. These linkers are functionalised with an azide moiety for use in CuAAC coupling to alkynyl derivatives of bioactive small molecules and have been modified to include photoreactive groups giving a series of linkers for use in the identification of less abundant, or low affinity, proteins. The first drug investigated, anisomycin (ANS), is a small molecule which was initially introduced as an antibiotic drug (Flagecidin). At nanomolar concentrations ANS has been shown to affect the mitogen activated protein kinase (MAPK) pathways; downstream effects of these pathways are thought to play a role in a range of pathological disorders such as Alzheimer’s disease, cancer and spinal muscular atrophy (SMA). ANS is thus a candidate for drug repurposing. Although the downstream effects of MAPK/SAPK pathway activation induced by anisomycin are well-documented, the cellular target has yet to be revealed. Previous work by the Hulme group has shown that the N-propargyl anisomycin derivative (I) retains the biological activity of the lead compound ANS. Thus to evaluate the cellular protein targets, N-propargyl ANS (I) was coupled onto the linker toolbox to create an ANS affinity probe library as described in chapter 2. The second drug investigated, fingolimod, was introduced as an immunomodulating drug (Glienya) for the treatment of multiple sclerosis (MS). This small molecule has also been shown to have anti-cancer properties in a range of cancer cell lines; however the precise mechanism by which this is effected is unknown. Literature precedent shows that terminal modification of fingolimod generates analogues which still retain biological activity. Thus a novel fingolimod alkyne derivative (II) was synthesised and used to create an affinity probe library as described in chapter 3. Chapter 4 describes affinity pull-down experiments conducted with the aim of finding the protein target(s) of ANS and fingolimod, using the affinity probe libraries generated in chapters 2 and 3. This chapter concludes with a discussion of the implications of these findings and directions for future study.
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Role of p38 and STAT5 Kinase Pathways in the Regulation of Survival of Motor Neuron Gene Expression for Development of Novel Spinal Muscular Atrophy TherapeuticsFarooq, Faraz T 17 July 2012 (has links)
Spinal muscle atrophy (SMA) is an autosomal recessive neurodegenerative disease which is characterized by the loss of α motor neurons from the anterior horn of the spinal cord, resulting in progressive muscle atrophy. The loss of functional Survival motor neuron (SMN) protein due to mutations or deletion in the SMN1 gene is the cause of SMA. A potential treatment strategy for SMA is to upregulate levels of the SMN protein originating from the copy gene SMN2 which can compensate in part for the absence of the functional SMN1 gene. I have shown a novel therapeutic strategy for SMA treatment through the activation of the p38 pathway by the bacterial antibiotic anisomycin which stabilizes and increases SMN mRNA levels in vitro. Activation of the p38 pathway by anisomycin leads to cytoplasmic accumulation of HuR protein which binds to the 3’UTR of SMN transcript resulting in increased SMN levels. This opens up a novel potential therapeutic strategy for SMA. I have also identified and demonstrated a significant induction of SMN protein levels in vitro and in vivo upon treatment with FDA approved drug celecoxib, which also activates the p38 pathway. Celecoxib mitigates disease severity along with increasing the lifespan of SMA mice. Sodium valproate, trichostatin A and aclarubicin, all agents which effectively enhance SMN2 expression, have been recently shown to activate STAT5 in SMA-like mouse embryonic fibroblasts and human SMN2-transfected NSC34 cells. Given that prolactin is also known to activate the STAT5 signalling pathway, can cross blood brain barrier and is FDA approved, we elected to assess its impact on SMN levels. In this manner, I have demonstrated a significant induction in SMN mRNA and protein levels in neuronal NT2 and MN-1 cells upon treatment with prolactin. I have also demonstrated that activation of the STAT5 pathway by prolactin is necessary for this transcriptional upregulation of the SMN gene. I have found that prolactin treatment induces SMN expression in brain and spinal cord samples and that it ameliorates the disease phenotype, improving motor neuron function and increasing survival in the SMA mouse model. Presently there is no cure for SMA. This study will help in the identification and characterization of potential therapeutic compounds for the treatment of SMA.
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Role of p38 and STAT5 Kinase Pathways in the Regulation of Survival of Motor Neuron Gene Expression for Development of Novel Spinal Muscular Atrophy TherapeuticsFarooq, Faraz T January 2012 (has links)
Spinal muscle atrophy (SMA) is an autosomal recessive neurodegenerative disease which is characterized by the loss of α motor neurons from the anterior horn of the spinal cord, resulting in progressive muscle atrophy. The loss of functional Survival motor neuron (SMN) protein due to mutations or deletion in the SMN1 gene is the cause of SMA. A potential treatment strategy for SMA is to upregulate levels of the SMN protein originating from the copy gene SMN2 which can compensate in part for the absence of the functional SMN1 gene. I have shown a novel therapeutic strategy for SMA treatment through the activation of the p38 pathway by the bacterial antibiotic anisomycin which stabilizes and increases SMN mRNA levels in vitro. Activation of the p38 pathway by anisomycin leads to cytoplasmic accumulation of HuR protein which binds to the 3’UTR of SMN transcript resulting in increased SMN levels. This opens up a novel potential therapeutic strategy for SMA. I have also identified and demonstrated a significant induction of SMN protein levels in vitro and in vivo upon treatment with FDA approved drug celecoxib, which also activates the p38 pathway. Celecoxib mitigates disease severity along with increasing the lifespan of SMA mice. Sodium valproate, trichostatin A and aclarubicin, all agents which effectively enhance SMN2 expression, have been recently shown to activate STAT5 in SMA-like mouse embryonic fibroblasts and human SMN2-transfected NSC34 cells. Given that prolactin is also known to activate the STAT5 signalling pathway, can cross blood brain barrier and is FDA approved, we elected to assess its impact on SMN levels. In this manner, I have demonstrated a significant induction in SMN mRNA and protein levels in neuronal NT2 and MN-1 cells upon treatment with prolactin. I have also demonstrated that activation of the STAT5 pathway by prolactin is necessary for this transcriptional upregulation of the SMN gene. I have found that prolactin treatment induces SMN expression in brain and spinal cord samples and that it ameliorates the disease phenotype, improving motor neuron function and increasing survival in the SMA mouse model. Presently there is no cure for SMA. This study will help in the identification and characterization of potential therapeutic compounds for the treatment of SMA.
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Cutaneous p38 mitogen-activated protein kinase activation triggers psoriatic dermatitis / 皮膚でのp38MAPK活性化が乾癬様皮膚炎を引き起こすSakurai, Kenji 23 January 2020 (has links)
京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22150号 / 医博第4541号 / 新制||医||1039(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 竹内 理, 教授 稲垣 暢也, 教授 杉田 昌彦 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM
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New Methodologies in Organic Chemistry: Applications to the Synthesis of α-Amino Acids and Natural ProductsHirner, Sebastian January 2009 (has links)
This thesis deals with the development and application of new synthetic methodology in organic chemistry. The first part describes the development of a new protocol for the synthesis of 3-pyrrolines by means of a microwave-assisted ring-expansion reaction of 2-vinylaziridines. In addition, this methodology is implemented as a key-step in a formal total synthesis of the antibiotic (-)-anisomycin. In the second part, a new methodology for the synthesis of arylglycines from Weinreb amides is described. In this procedure, a Grignard reagent is added to the iminium ion formed from the Weinreb amide upon treatment with a base. When a chiral amide is used, the nucleophilic addition proceeds with high diastereoselectivity. Finally, an easy and straightforward synthesis of α-amino amides via a base-mediated rearrangement of modified Weinreb amides into N,O-acetals is presented. Subsequent arylation, alkylation, alkenylation or alkynylation of this intermediate affords the corresponding α-amino amides in excellent yields. Furthermore, a more generalized protocol for the α-arylation of Weinreb amides lacking an α-amino moiety is also discussed. / QC 20100719
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Neglected tropical disease therapy through exploration of novel points of intervention for combating resistant parasitesNguyen, Anh Minh Thao 11 1900 (has links)
Les maladies tropicales négligées, causées par des trypanosomes telles que la leishmaniose, la
trypanosomiase africaine (maladie du sommeil) et la trypanosomiase américaine (la maladie de
Chagas), imposent une morbidité et un taux de mortalité graves ayant un grand impact sur les
populations les plus pauvres. Les traitements contemporains de ces maladies sont limités en raison
des effets secondaires toxiques et de l’émergence des souches résistantes. Dans le but de répondre
au besoin croissant de traitement, l’exploration de nouveaux agents antiprotozoaires est donc plus
que nécessaire. La recherche décrite dans cette thèse vise à développer une nouvelle thérapie pour
traiter ces infections parasitaires en ciblant de multiples fonctions vitales pour la survie du parasite.
Une série de peptides, petites molécules et combinaison de peptides et petites molécules
conjugués ont été préparés et étudiés. Par exemple, les lipopeptides almiramides N-méthylés
présentent une activité antiparasitaire avec un indice thérapeutique élevé en ciblant le glycosome,
un organite typique des trypanosomes. Une étude de la relation structure-activité a été réalisée
pour examiner l’influence de la N-méthylation et de la conformation sur l’activité contre diverses
souches de Leishmania et sur la cytotoxicité. La synthèse et l’analyse biologique de vingt-cinq
analogues ont démontré que les dérivés portant un acide aminé Na-méthylé aux deux extrémités
présentaient une activité supérieure à celle des peptides perméthylés et une puissance relativement
élevée contre les souches résistantes. Le remplacement des résidus d’acides aminés dans le peptide
par un α-amino γ-lactam (Agl) et N-aminoimidazalone (Nai) réduit l’activité antiparasitaire;
cependant, les amides peptidiques possédant des résidus d’Agl à la deuxième position conservaient
une puissance significative dans les séries non méthylées et perméthylées. L’étude systématique
des effets de la N-méthylation et de la géométrie de tour sur l’activité antiparasitaire a montré la
pertinence d’un conformère étendu sur les résidus centraux et la mobilité conformationnelle par
isomérisation des amides tertiaires et la géométrie des tours aux extrémités des peptides actifs.
L’alcaloïde naturel anisomycine a été étudié en raison de son importance en tant qu’inhibiteur
de la synthèse des protéines avec une vaste activité antiparasitaire. L’évaluation des relations
structure-activité antiprotozoaires de l’anisomycine a été réalisée en modifiant les groupements
fonctionnels du cycle de pyrrolidine ainsi que sa partie aromatique. L’examination de la
cytotoxicité et l’activité antiprotozoaire contre diverses souches de Leishmania en comparant avec
le produit naturel ont révélé une stratégie de préparation d’analogues à forte puissance et à faible
toxicité pour l’hôte. L’étude préliminaire de l’activité antiprotozoaire et de la sélectivité a favorisé
ii
l’exploration de conjugués phénoliques de l’anisomycine. Une série d’analogues de l’anisomycine
ont été synthétisés en conjuguant l’anisomycine sur des peptides almiramides et des résidus
d’acides aminés qui peuvent respectivement cibler les fonctions glycosome et transporteur du
parasite. La cytotoxicité et l’activité antiprotozoaire contre diverses souches de Leishmania,
Trypanosoma brucei et Trypanosoma cruzi ont démontré que la conjugaison de divers acides
aminés et résidues insaturées donnait des agents antiparasitaires prometteurs qui ciblaient
sélectivement les différents parasites avec une cytotoxité minimale en comparaison avec celle du
produit naturel.
L’activité antiprotozoaire de l’anisomycine et de ses dérivés a incité à poursuivre l’exploration
des relations structure-activité pour le développement d’un traitement antiparasitaire. Compte tenu
de l’utilité de l’anisomycine dans cette étude, une synthèse formelle du produit naturel a été
développée. En utilisant la (2S,4R)-4-hydroxyproline comme précurseur chiral peu coûteux, une
voie de synthèse a été développée impliquant le couplage Negishi. L’introduction dans les
analogues de la décacéoxy-anisomycine a également été réalisée par un protocole similaire.
Les études de relation structure-activité des peptides almiramides et des analogues de
l’anisomycine décrites dans cette thèse ont ouvert une voie prometteuse pour le développement de
nouveaux agents antiparasitaires à haute puissance et à faible toxicité pour l’hôte. En ciblant
plusieurs points d’intervention, les nouveaux agents offrent la promesse de ralentir les modes de
résistance. En outre, la synthèse d’analogues désacétoxy-anisomycine a ouvert la porte à des
intermédiaires clés pour une exploration plus approfondie des dérivés de l’anisomycine et pour
améliorer la synthèse de prototypes thérapeutiques afin de relever des défis importants dans
l’atténuation des maladies tropicales négligées. / Neglected Tropical Diseases (NTDs) which are caused by trypasonomatid infections, such as
leishmaniasis, human African trypanosomiasis (HAT) and Chagas disease are known to inflict
serious morbidity and mortality with greatest impact on the poorest populations. Contemporary
anti-trypanosomatid therapy is limited due to toxic side effects and the rise of resistant stains. A
growing need has emerged for novel anti-protozoal agents. The research described in this thesis
seeks to develop novel therapy to treat trypasonomatid infection by targeting multiple vital
functions for parasite survival.
A series of peptide, small molecule, and peptide-small molecule conjugates have been prepared
and studied. For example, the almiramide N-methylated lipo-peptides exhibit anti-parasitic activity
with high therapeutic index by targeting the glycosome, an organelle without a mammalian
counterpart. A structure-activity relationship study has been performed to examine the influences
of N-methylation and conformation on activity against various strains of leishmaniasis protozoan
and on cytotoxicity. The synthesis and biological analysis of twenty-five analogs demonstrated
that derivatives with a single methyl group on specific residue amide nitrogen exhibited greater
activity than the permethylated peptides and relatively high potency against resistant strains.
Replacement of amino amide residues in the peptide by turn inducing α-amino γ-lactam (Agl) and
N-aminoimidazalone (Nai) counterparts reduced typically anti-parasitic activity; however, peptide
amides possessing Agl residues at the second residue retained significant potency in the
unmethylated and permethylated series. Systematic study of the effects of methylation and turn
geometry on anti-parasitic activity indicated the relevance of an extended conformer about the
central residues and conformational mobility by tertiary amide isomerization and turn geometry at
the extremities of the active peptides.
The natural alkaloid anisomycin was studied because of significance as a protein synthesis
inhibitor with broad anti-parasitic activity. Assessment of the structure - anti-protozoan activity
relationships of anisomycin was performed by modifying pyrrolidine and aromatic functional
groups. Examination of cytotoxicity and antiprotozoal activity against various strains of
Leishmania and comparison with the natural product revealed a strategy for preparing analogs with
high potency and low host toxicity. The preliminary study of antiprotozoal activity and selectivity
promoted the exploration phenolic conjugates of anisomycin. A serie of anisomycin analogs were
synthesized by conjugating anisomycin onto almiramide peptides and amino acids residues which
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may respectively target the glycosome and transporter functions of the parasite. The cytotoxicity
and antiprotozoal activity against various strains of Leishmania, Trypanosoma brucei and
Trypanosoma cruzi demonstrated that conjugation of various amino acid and unsaturated moieties
yielded promising agents that selectively targeted the different parasites with minimal cytotoxity
compared to that of the natural product.
The antiprotozoal activity of anisomycin and derivatives has led to a better understanding of
structure-activity relationships for the development of anti-parasitic therapy. Considering the
utility of anisomycin in this study, a formal synthesis of the natural product was developed.
Employing (2S,4R)-4-hydroxyproline as an inexpensive chiral building block, a route was
conceived featuring the Negishi coupling. Entry into deacteoxy-anisomycin analogs was also
achieved by a similar protocol.
The structure-activity relationship studies of almiramide peptides and anisomycin analogs
described in this thesis have opened a promissing gateway for developing new anti-parasitic agents
with high potency and low host toxicity. By targeting multiple points of intervention, the new
agents offer promise to minimize modes of resistance. Moreover, the synthesis of deacetoxyanisomycin
analogs has paved the way to key intermediates for further exploration of anisomycin
derivatives and for improving the synthesis of therapeutic prototypes to tackle important
challenges in mitigating Neglected Tropical Diseases.
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Mécanismes de plasticité synaptique dans l’amygdale lors de la réactivation de la mémoire de peur auditive chez le rat : interaction dynamique des récepteurs NMDA et AMPABen Mamou, Cyrinne 07 1900 (has links)
La plasticité synaptique est une propriété indispensable à l’acquisition de la mémoire chez toutes les espèces étudiées, des invertébrés aux primates. La formation d’une mémoire débute par une phase de plasticité qui inclut une restructuration synaptique ; ensuite elle se poursuit par la consolidation de ces modifications, contribuant à la mémoire à long terme. Certaines mémoires redeviennent malléables lorsqu’elles sont rappelées. La trace mnésique entre alors dans une nouvelle de phase de plasticité, au cours de laquelle certaines composantes de la mémoire peuvent être mises à jour, puis reconsolidées. L’objectif de la présente thèse est d’étudier les mécanismes cellulaires et moléculaires qui sont activés lors du rappel d’une mémoire. Nous avons utilisé un modèle de conditionnement Pavlovien, combiné à l’administration d’agents pharmacologiques et à l’analyse quantitative de marqueurs de plasticité synaptique, afin d’étudier la dynamique de la mémoire de peur auditive chez des rats Sprague Dawley. La circuiterie neuronale et les mécanismes associatifs impliqués dans la neurobiologie de cette mémoire sont bien caractérisés, en particulier le rôle des récepteurs glutamatergiques de type NMDA et AMPA dans la plasticité synaptique et la consolidation. Nos résultats démontrent que le retour de la trace mnésique à un état de labilité nécessite l’activation des récepteurs NMDA dans l’amygdale baso-latérale à l’instant même du rappel, alors que les récepteurs AMPA sont requis pour l’expression comportementale de la réponse de peur conditionnée. D’autre part, les résultats identifient le rappel comme une phase bien plus dynamique que présumée, et suggèrent que l’expression de la peur conditionnée mette en jeu la régulation du trafic des récepteurs AMPA par les récepteurs NMDA. Le présent travail espère contribuer à la compréhension de la neurobiologie fondamentale de la mémoire. De plus, il propose une intégration des résultats aux modèles animaux d’étude des troubles psychologiques conséquents aux mémoires traumatiques chez l’humain, tels que les phobies et les syndromes de stress post-traumatiques. / Synaptic plasticity is necessary for the acquisition of memory in all studied species, from invertebrates to primates. Memory formation starts with a phase of plasticity that entails synaptic remodeling ; then follows the consolidation of these modifications, which contributes to long-term memory. Some memories return to a malleable state upon retrieval. Consequently, the memory trace enters a new phase of plasticity, during which some memory components are eventually updated, then reconsolidated. The aim of the present thesis was to study the cellular and molecular mechanisms that are engaged during memory retrieval. We used a model of Pavlovian conditioning in Sprague Dawley rats, combined to pharmacological manipulations and quantitative analysis of synaptic plasticity markers, in order to study the dynamics of auditory fear memory. The neuronal circuitry and the associative mechanisms involved in the neurobiology of this memory are well characterized, in particular the role of NMDA and AMPA glutamatergic receptors in synaptic plasticity and consolidation. Our results show that the return of the memory trace to lability requires activation of NMDA receptors in the basolateral amygdala during retrieval, whereas AMPA receptors are necessary for the behavioral expression of the conditioned fear response. Furthermore, the data identify retrieval as being much more dynamic than recognized, and suggest that conditioned fear expression involves NMDA receptor-dependent regulation of AMPA receptors’ trafficking. The present work attempts to advance our understanding of the fundamental neurobiology of memory. In addition, it offers an integrative view of the data with regards to animal modeling of human clinical issues related to traumatic memories, like phobias and post-traumatic stress disorders.
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Mécanismes de plasticité synaptique dans l’amygdale lors de la réactivation de la mémoire de peur auditive chez le rat : interaction dynamique des récepteurs NMDA et AMPABen Mamou, Cyrinne 07 1900 (has links)
La plasticité synaptique est une propriété indispensable à l’acquisition de la mémoire chez toutes les espèces étudiées, des invertébrés aux primates. La formation d’une mémoire débute par une phase de plasticité qui inclut une restructuration synaptique ; ensuite elle se poursuit par la consolidation de ces modifications, contribuant à la mémoire à long terme. Certaines mémoires redeviennent malléables lorsqu’elles sont rappelées. La trace mnésique entre alors dans une nouvelle de phase de plasticité, au cours de laquelle certaines composantes de la mémoire peuvent être mises à jour, puis reconsolidées. L’objectif de la présente thèse est d’étudier les mécanismes cellulaires et moléculaires qui sont activés lors du rappel d’une mémoire. Nous avons utilisé un modèle de conditionnement Pavlovien, combiné à l’administration d’agents pharmacologiques et à l’analyse quantitative de marqueurs de plasticité synaptique, afin d’étudier la dynamique de la mémoire de peur auditive chez des rats Sprague Dawley. La circuiterie neuronale et les mécanismes associatifs impliqués dans la neurobiologie de cette mémoire sont bien caractérisés, en particulier le rôle des récepteurs glutamatergiques de type NMDA et AMPA dans la plasticité synaptique et la consolidation. Nos résultats démontrent que le retour de la trace mnésique à un état de labilité nécessite l’activation des récepteurs NMDA dans l’amygdale baso-latérale à l’instant même du rappel, alors que les récepteurs AMPA sont requis pour l’expression comportementale de la réponse de peur conditionnée. D’autre part, les résultats identifient le rappel comme une phase bien plus dynamique que présumée, et suggèrent que l’expression de la peur conditionnée mette en jeu la régulation du trafic des récepteurs AMPA par les récepteurs NMDA. Le présent travail espère contribuer à la compréhension de la neurobiologie fondamentale de la mémoire. De plus, il propose une intégration des résultats aux modèles animaux d’étude des troubles psychologiques conséquents aux mémoires traumatiques chez l’humain, tels que les phobies et les syndromes de stress post-traumatiques. / Synaptic plasticity is necessary for the acquisition of memory in all studied species, from invertebrates to primates. Memory formation starts with a phase of plasticity that entails synaptic remodeling ; then follows the consolidation of these modifications, which contributes to long-term memory. Some memories return to a malleable state upon retrieval. Consequently, the memory trace enters a new phase of plasticity, during which some memory components are eventually updated, then reconsolidated. The aim of the present thesis was to study the cellular and molecular mechanisms that are engaged during memory retrieval. We used a model of Pavlovian conditioning in Sprague Dawley rats, combined to pharmacological manipulations and quantitative analysis of synaptic plasticity markers, in order to study the dynamics of auditory fear memory. The neuronal circuitry and the associative mechanisms involved in the neurobiology of this memory are well characterized, in particular the role of NMDA and AMPA glutamatergic receptors in synaptic plasticity and consolidation. Our results show that the return of the memory trace to lability requires activation of NMDA receptors in the basolateral amygdala during retrieval, whereas AMPA receptors are necessary for the behavioral expression of the conditioned fear response. Furthermore, the data identify retrieval as being much more dynamic than recognized, and suggest that conditioned fear expression involves NMDA receptor-dependent regulation of AMPA receptors’ trafficking. The present work attempts to advance our understanding of the fundamental neurobiology of memory. In addition, it offers an integrative view of the data with regards to animal modeling of human clinical issues related to traumatic memories, like phobias and post-traumatic stress disorders.
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