Lipid transfer proteins (LTPs) belong to the pathogenesis-related protein family (PR-14) and are thought to participate in plant defense mechanisms. In this study, we characterize the function of an Arabidopsis thaliana mutant ltp12 (AT3G51590), a homologous lipid transfer protein to SIP470 from Nicotiana tabacum for its role in abiotic and biotic stress. SIP470, a lipid transfer protein, was found to interact with SABP2 in a yeast-two hybrid screen. SABP2 in tobacco is required for inducing a robust SAR response. The objective of this research is to understand the role of LTP12 in mediating abiotic stress as salicylic acid plays an important role in both abiotic and biotic stress in plants. For this research, stressor chemicals, NaCl (salinity), mannitol (osmotic stress), and drought (no water or PEG) will be used. Seedlings were initially germinated and grown on artificial plant growth MS media. The similar-sized young seedlings were transferred to MS media plates supplemented with or without stressor chemicals. Oxidative stress analysis of various antioxidant enzymes, such as catalase (CAT), superoxide dismutase (SOD), and peroxidase (POD) will be performed. The Na+ homeostasis for salinity stress will be studied using CoroNaTM dye and confocal microscopy. Our lab has T-DNA insertion knockout mutants of LTP12 that we will be used in the proposed studies. Here, we hypothesize that mutant ltp12 plants will be hypersensitive to abiotic stressors like NaCl, mannitol, and drought, while wildtype Col-0 will be markedly more tolerant. Reports also suggest that knockout lines of other lipid transfer proteins show a defective growth phenotype and lower expression of systemic acquired resistance (SAR). Moreover, to gain a better understanding of both lines' responses to abiotic stress, we need to carry out further studies on the soil as well. The study will also discuss the subcellular localization of ltp12 in Arabidopsis, which will provide an idea of its functional mechanism. Understanding the role of lipid transfer proteins can lead to the development of transgenic plants that are more tolerant to abiotic stresses and climate change.

Yes / The ability to either erase or update the memories of a previously learned spatial task is an essential process that is required to modify behaviour in a changing environment. Current evidence suggests that the neural representation of such cognitive flexibility involves the balancing of synaptic potentiation (acquisition of memories) with synaptic depression (modulation and updating previously acquired memories). Here we demonstrate that the p38 MAPK/MAPK-activated protein kinase 2 (MK2) cascade is required to maintain the precise tuning of long-term potentiation and long-term depression at CA1 synapses of the hippocampus which is correlated with efficient reversal learning. Using the MK2 knockout (KO) mouse, we show that mGluR-LTD, but not NMDAR-LTD, is markedly impaired in mice aged between 4 and 5 weeks (juvenile) to 7 months (mature adult). Although the amplitude of LTP was the same as in wildtype mice, priming of LTP by the activation of group I metabotropic receptors was impaired in MK2 KO mice. Consistent with unaltered LTP amplitude and compromised mGluR-LTD, MK2 KO mice had intact spatial learning when performing the Barnes maze task, but showed specific deficits in selecting the most efficient combination of search strategies to perform the task reversal. Findings from this study suggest that the mGluR-p38-MK2 cascade is important for cognitive flexibility by regulating LTD amplitude and the priming of LTP. / Professor Richard Greene at the University of Bradford - startup fund to setup electrophysiological facility and Wellcome Trust 200646/Z/16/Z to S.A.L.C.

La mémoire et l’apprentissage sont des phénomènes complexes dont on ne comprend pas encore bien l’origine au niveau cellulaire et moléculaire. Cependant, il est largement admis que des changements plus simples au niveau synaptique, tels que la potentialisation à long-terme (long-term potentiation ou LTP) pourraient constituer la base cellulaire de la formation des nouveaux souvenirs. Ces mécanismes sont couramment étudiés au niveau de l’hippocampe, une région du lobe temporal reconnue comme étant nécessaire à la formation de la mémoire explicite chez les mammifères. La LTP est classiquement définie comme un renforcement durable de l’efficacité de connexions synaptiques ayant été stimulées de façon répétée et soutenue. De plus, on peut distinguer deux formes de LTP: une LTP précoce, qui repose sur la modification de protéines déjà formées, et une LTP tardive, qui requiert, elle, la synthèse de nouvelles protéines. Cependant, bien que de nombreuses études se soient intéressées au rôle de la traduction pour la maintenance de la LTP, les mécanismes couplant l’activité synaptique à la machinerie de synthèse protéique, de même que l’identité des protéines requises sont encore peu connus. Dans cette optique, cette thèse de doctorat s’est intéressée aux interactions entre l’activité synaptique et la régulation de la traduction. Il est par ailleurs reconnu que la régulation de la traduction des ARNm eukaryotiques se fait principalement au niveau de l’initiation. Nous avons donc étudié la modulation de deux voies majeures pour la régulation de la traduction au cours de la LTP : la voie GCN2/eIF2α et la voie mTOR. Ainsi, nos travaux ont tout d’abord démontré que la régulation de la voie GCN2/eIF2α et de la formation du complexe ternaire sont nécessaires à la maintenance de la plasticité synaptique et de la mémoire à long-terme. En effet, l’activité synaptique régule la phosphorylation de GCN2 et d’eIF2α, ce qui permet de moduler les niveaux du facteur de transcription ATF4. Celui-ci régule à son tour la transcription CREB-dépendante et permet ainsi de contrôler les niveaux d’expression génique et la synthèse de protéines nécessaires pour la stabilisation à long-terme des modifications synaptiques. De plus, la régulation de la voie mTOR et de la traduction spécifique des ARNm 5’TOP semble également jouer un rôle important pour la plasticité synaptique à long-terme. La modulation de cette cascade par l’activité synaptique augmente en effet spécifiquement la capacité de traduction des synapses activées, ce qui leur permet de traduire et d’incorporer les protéines nécessaires au renforcement durable des synapses. De telles recherches permettront sans doute de mieux comprendre la régulation des mécanismes traductionnels par l’activité synaptique, ainsi que leur importance pour la maintenance de la potentialisation à long-terme et de la mémoire à long-terme. / Learning and memory are complex processes that are not yet fully understood at the cellular and molecular levels. It is however widely accepted that persistent modifications of synaptic connections, like long-term potentiation (LTP), could be responsible for the encoding of new memories. These changes are frequently studied in the hippocampus, a temporal lobe structure that as been shown to be necessary for explicit memory in mammals. Long-term potentiation is classically defined as a persistent and stable modification of synaptic connections that have been repeatedly stimulated. Moreover, there are two different phases of LTP: an early-LTP, that only requires the modification of pre-existing proteins, and a late-LTP, that requires the synthesis of new proteins. Numerous studies have evaluated the role of new protein synthesis for the persistence of LTP, however, the mechanisms coupling synaptic activity and the translational machinery, as well as the identity of the necessary proteins are not yet fully understood. From this perspective, this Ph.D. thesis has evaluated the interactions between synaptic activity and the regulation of translation. As it is widely accepted that the regulation of translation is primarily at the initiation level, we therefore investigated the modulation of two major pathways for the regulation of translation during LTP: the GCN2/eIF2α pathway and the mTOR pathway. First, our studies have shown that the regulation of the GCN2/eIF2α pathway and of the ternary complex formation are necessary for the long-term maintenance of synaptic plasticity and memory. Indeed, synaptic activity regulates GCN2 and eIF2α phosphorylation, which modulates the transcription factor ATF4 levels. ATF4 in turn regulates CREB-dependent transcription, and therefore controls the levels of genetic expression and the synthesis of new proteins necessary for the long-term stabilization of synaptic modifications. Moreover, the regulation of the mTOR pathway and of the specific translation of 5’TOP mRNAs likely also play an important role for long-term synaptic plasticity. Modulation of this cascade by synaptic activity specifically increases the translational capacity of activated synapses, allowing them to translate and incorporate the necessary proteins for the lasting reinforcement of synapses. These studies will undoubtedly help to understand the regulation of translational mechanisms by synaptic activity and their significance for the maintenance of long-term potentiation and long-term memory.

Recent literature has shown that AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors lacking the GluR2 subunit (thus calcium permeable) are widely expressed in the CNS, especially in interneurons and glia, where they contribute to synaptic transmission and plasticity. Studies have also indicated that calcium permeable AMPARs (CP-AMPARs) are expressed and participate in synaptic regulation in principal neurons, including hippocampal pyramidal neurons. Furthermore, CP-AMPARs and their resultant calcium influx are implicated in various pathophysiological conditions such as ischemia and seizures. However, the synaptic events activated by calcium influx through CP-AMPARs remain unknown. I took advantage of genetically altered mice without (GluR2-/-) or with reduced GluR2 (GluR2+/-), thus allowing the expression and detailed analysis of synaptic CP-AMPARs in hippocampal pyramidal neurons. Utilizing electrophysiological techniques, I demonstrated that these receptors were capable of inducing numerous forms of long-term potentiation (referred to as CP-AMPAR-dependent LTP) through a number of different induction protocols, including high-frequency stimulation (HFS) and theta-burst stimulation (TBS). This included a previously undemonstrated form of protein-synthesis dependent late-LTP (L-LTP) at CA1 synapses that is NMDA-receptor (NMDAR) independent. This form of plasticity was completely blocked by the selective CP-AMPAR inhibitor IEM-1460. Surprisingly, calcium/calmodulin-dependent kinase II (CaMKII), the key protein kinase that is indispensable for NMDAR-dependent LTP at CA1 synapses appeared to be not required for the induction of CP-AMPAR-dependent LTP due to the lack of effect of two separate pharmacological inhibitors (KN-62 and staurosporine) on this form of potentiation. Both KN-62 and staurosporine strongly inhibited NMDAR dependent LTP in control studies. In contrast, inhibitors for the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) cascade (PD98059 and U0126) significantly attenuated this CP-AMPAR-dependent LTP. Additional studies with knockout mice revealed that the ERK/MAPK signalling cascade is likely acting through p-21 activated kinase 1 (or PAK1, a Rho-GTPase associated kinase) dependent mechanisms. These results suggest that distinct synaptic signalling underlies GluR2-lacking CP-AMPAR-dependent LTP, and reinforces the recent notions that CP-AMPARs are important facilitators of synaptic plasticity in the brain.

Recent literature has shown that AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors lacking the GluR2 subunit (thus calcium permeable) are widely expressed in the CNS, especially in interneurons and glia, where they contribute to synaptic transmission and plasticity. Studies have also indicated that calcium permeable AMPARs (CP-AMPARs) are expressed and participate in synaptic regulation in principal neurons, including hippocampal pyramidal neurons. Furthermore, CP-AMPARs and their resultant calcium influx are implicated in various pathophysiological conditions such as ischemia and seizures. However, the synaptic events activated by calcium influx through CP-AMPARs remain unknown. I took advantage of genetically altered mice without (GluR2-/-) or with reduced GluR2 (GluR2+/-), thus allowing the expression and detailed analysis of synaptic CP-AMPARs in hippocampal pyramidal neurons. Utilizing electrophysiological techniques, I demonstrated that these receptors were capable of inducing numerous forms of long-term potentiation (referred to as CP-AMPAR-dependent LTP) through a number of different induction protocols, including high-frequency stimulation (HFS) and theta-burst stimulation (TBS). This included a previously undemonstrated form of protein-synthesis dependent late-LTP (L-LTP) at CA1 synapses that is NMDA-receptor (NMDAR) independent. This form of plasticity was completely blocked by the selective CP-AMPAR inhibitor IEM-1460. Surprisingly, calcium/calmodulin-dependent kinase II (CaMKII), the key protein kinase that is indispensable for NMDAR-dependent LTP at CA1 synapses appeared to be not required for the induction of CP-AMPAR-dependent LTP due to the lack of effect of two separate pharmacological inhibitors (KN-62 and staurosporine) on this form of potentiation. Both KN-62 and staurosporine strongly inhibited NMDAR dependent LTP in control studies. In contrast, inhibitors for the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) cascade (PD98059 and U0126) significantly attenuated this CP-AMPAR-dependent LTP. Additional studies with knockout mice revealed that the ERK/MAPK signalling cascade is likely acting through p-21 activated kinase 1 (or PAK1, a Rho-GTPase associated kinase) dependent mechanisms. These results suggest that distinct synaptic signalling underlies GluR2-lacking CP-AMPAR-dependent LTP, and reinforces the recent notions that CP-AMPARs are important facilitators of synaptic plasticity in the brain.

No description available.

Made available in DSpace on 2014-12-17T15:16:04Z (GMT). No. of bitstreams: 1 AnaCLN.pdf: 1365991 bytes, checksum: a91aa932e949e0fb6e624f6ad5057083 (MD5) Previous issue date: 2009-07-02 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / The locomotion is one of the most important capabilities developed by the animals, whose improvement is dependent on several neural centers, including the spinal cord. This activity promotes a lot of spinal modifications that enable it to adapt and improve their connections. This study aimed to observe the morphological changes occurring in the spinal cord after locomotor training in intact rats. For that we used male Wistar rats, which were submitted to locomotor training in wheel activity in protocols 1, 3 and 7 days (30min/day), and the results were compared to a control group not subjected to exercise. Coronal sections of 40 μm of the lumbosacral spinal cord were subjected to immunohistochemical techniques anti-Egr1, anti-NMDA and anti-SP, to characterize the spinal plasticity related to these substances. Egr1-immunoreactive cells were increased in all laminas, essentially in those more intensely activated by locomotion, laminas IV-X levels L4-S3. All observed sections expressed NMDA-immunoreactivity. Analysis of SP in the spinal dorsal horn resulted no significant variations of this neuropeptide related to locomotion. The results suggest that locomotor training provides synaptic plasticity similar to LTP in all laminas of the lumbosacral spinal cord, in different intensities. However, the SP appears do not participate of this process in the spinal dorsal horn. This work will contribute for consolidating and characterization of synaptic plasticity in the spinal cord / A locomo??o ? uma das mais importantes capacidades desenvolvidas pelos animais, cujo aperfei?oamento ? dependente de v?rios centros neurais, incluindo a medula espinal. Esta atividade promove v?rias modifica??es espinais que a possibilita se adaptar e aperfei?oar suas conex?es. Este trabalho teve por objetivo observar as altera??es morfol?gicas ocorridas na medula espinal ap?s o treinamento locomotor de ratos intactos. Para isso foram utilizados ratos Wistar machos, os quais foram submetidos ao treinamento locomotor na roda de atividade em protocolos de 1, 3 e 7 dias (30min/dia), e os resultados foram comparados aos de um grupo controle, n?o submetido ao exerc?cio. Cortes coronais de 40 μm da medula espinal lombossacral foram submetidos a t?cnicas imunohistoquimicas anti-Egr1, anti-NMDA e anti-SP, para caracterizarmos a plasticidade espinal quanto a essas subst?ncias. C?lulas imunorreativas a Egr1 estavam aumentadas em todas as l?minas, intensamente nas regi?es mais ativadas pela locomo??o, l?minas IV-X dos n?veis L4-S3. Todas as sec??es observadas expressaram imunorreatividade a NMDA. A an?lise da SP no corno dorsal espinal resultou em aus?ncia de varia??es significantes deste neuropept?deo relacionadas com a locomo??o. Diante dos resultados, sugerimos que o treinamento locomotor proporciona plasticidade sin?ptica semelhante a LTP em todas as l?minas da medula espinal, em intensidades diferenciadas. No entanto, esse processo parece n?o ter a participa??o da SP no corno dorsal espinal. Este trabalho vem contribuir para a consolida??o e caracteriza??o da plasticidade sin?ptica na medula espinal

The fragile X mental retardation protein (FMRP) is an important regulator of protein translation, and a lack of FMRP expression leads to a cognitive disorder known as fragile X syndrome (FXS). Clinical symptoms characterizing FXS include learning impairments and heightened anxiety in response to stressful situations. The Fmr1-/y mouse has previously been shown to have deficits in context discrimination and novel object recognition tasks, which primarily rely on the dentate gyrus (DG) region of the hippocampal formation, but not in the Morris water maze (MWM) or the elevated plus-maze tasks, which primarily depend on the Cornu Ammonis (CA1) region. Furthermore, previous research has demonstrated N-methyl-D-aspartate receptor (NMDAR)-associated synaptic plasticity impairments in the DG but not in the CA1. However, the impact of acute stress on synaptic plasticity in the Fmr1-/y hippocampus has not been examined. The current study sought to extend previous behavioural investigations in the Fmr1-/y mouse, as well as examine the impact of stress on activation of the hypothalamic-pituitary-adrenal (HPA)-axis and on hippocampal synaptic plasticity. To further characterize hippocampus-dependent behaviour in this mouse model, the DG-dependent metric change spatial processing and CA1-dependent temporal order discrimination tasks were evaluated. The results reported here support previous findings and demonstrate that Fmr1-/y mice have performance deficits in the DG-dependent task but not in the CA1-dependent task, suggesting that previously reported subregional differences in NMDAR-associated synaptic plasticity deficits in the hippocampus of the Fmr1-/y mouse model may also manifest as selective behavioural deficits in hippocampus-dependent tasks. In addition, following acute stress, mice lacking FMRP showed a faster elevation of the glucocorticoid corticosterone and a more immediate impairment in long-term potentiation (LTP) in the DG. Stress-induced LTP impairments were rescued by administering the glucocorticoid receptor (GR) antagonist RU38486. Administration of RU38486 also enhanced LTP in Fmr1-/y mice in the absence of acute stress to wild-type levels, and this enhancement was blocked by application of the NMDAR antagonist 2-amino-5-phosphonopentanoic acid. These results suggest that a loss of FMRP results in enhanced GR signalling that may adversely affect NMDAR-dependent synaptic plasticity in the DG. Finally, synaptic plasticity alterations reported in this work were found to be specific to the DG and were unidirectional, i.e., restricted to LTP, as NMDAR- and metabotropic glutamate receptor (mGluR)-LTD were both unaffected by acute stress in the DG or the CA1 regions. This study offers new insights into synaptic plasticity impairments in the Fmr1-/y mouse model, and suggests stress and GRs as important contributors to learning and memory deficits in FXS. / Graduate

Spontaneous activity in neuronal networks in vitro is common and has been well documented. However, alteration of spontaneous activity in such networks via conditioning electrical stimulation has received much less experimental attention. Two different patterns of electrical stimulation were used to enhance or depress the level of spontaneous activity in spinal cord cultures. High-frequency stimulation (HFS), a method routinely shown to increase the efficacy of synaptic transmission, was employed to augment spontaneous activity. Low-frequency stimulation (LFS), the technique often applied to depress synaptic efficacy, was employed to decrease spontaneous activity. In addition, LFS was used to reverse the effect of HFS on spontaneous activity. Likewise, HFS was applied to counter the effect of LFS. Because these networks were grown on multi-microelectrode plates (MMEPs), this allowed the simultaneous stimulation of any combination of the 64 electrodes in the array. Thus, the possible differences in response to single versus multi-electrode stimulation were also addressed. Finally, test-pulses were delivered before and after the conditioning stimulation on the same stimulation electrode(s) in order to assess the change in mean evoked action potentials (MEAPs). Dissociated spinal tissue from embryonic mice was allowed to mature into self-organized networks that exhibited spontaneous bursting activity after two weeks of incubation. Spontaneous activity was monitored from up to 14 recording channels simultaneously. Although uniform responses to stimulation across all recording electrodes were rarely observed, a large majority of the recording channels had similar responses. Spontaneous activity was increased in 52% of 89 HFS trials, whereas activity was decreased in 35% of 75 LFS trials. The duration of most of these increases was less than 5 minutes. When there were substantial and long-term (> 15 min) changes in spontaneous activity, the opposing stimulation pattern successfully reversed the effect of the previous stimulation. The percent change in MEAPs following conditioning stimulation suggested that synaptic modification had taken place in 75% of all test-pulse stimulation trials.

Alzheimer's disease is the most common type of dementia in the elderly; it is characterized by early deficits in learning and memory formation and ultimately leads to a generalised loss of higher cognitive functions. While amyloid beta (Aβ) and tau are traditionally associated with the development of Alzheimer disease, recent studies suggest that other factors, like the intracellular domain (APP-ICD) of the amyloid precursor protein (APP), could play a role. In this study, we investigated whether APP-ICD could affect synaptic transmission and synaptic plasticity in the hippocampus, which is involved in learning and memory processes. Our results indicated that overexpression of APP-ICD in hippocampal CA1 neurons leads to a decrease in evoked AMPA-receptor and NMDA-receptor dependent synaptic transmission. Our study demonstrated that this effect is specific for APP-ICD since its closest homologue APLP2-ICD did not reproduce this effect. In addition, APP-ICD blocks the induction of long term potentiation (LTP) and leads to increased of expression and facilitated induction of long term depression (LTD), while APLP2-ICD shows neither of these effects. Our study showed that this difference observed in synaptic transmission and plasticity between the two intracellular domains resides in the difference of one alanine in the APP-ICD versus a proline in the APLP2-ICD. Exchanging this critical amino-acid through point-mutation, we observed that APP(PAV)-ICD had no longer an effect on synaptic plasticity. We also demonstrated that APLP2(AAV)-ICD mimic the effect of APP-ICD in regards of facilitated LTD. Next we showed that the full length APP-APLP2-APP (APP with a substitution of the Aβ component for its homologous APLP2 part) had no effect on synaptic transmission or synaptic plasticity when compared to the APP-ICD. However, by activating caspase cleavage prior to induction of LTD or LTP, we observed an LTD facilitation and a block of LTP with APP-APLP2-APP, effects that were not seen with the full length APLP2 protein. APP is phosphorylated at threonine 668 (Thr668), which is localized directly after the aforementioned critical alanine and the caspase cleavage site in APP-APLP2-APP. Mutating this Thr668 for an alanine abolishes the effects on LTD and restores LTP induction. Finally, we showed that the facilitation of LTD with APP-APLP2-APP involves ryanodine receptor dependent calcium release from intracellular stores. Taken together, we propose the emergence of a new APP intracellular domain, which plays a critical role in the regulation of synaptic plasticity and by extension, could play a role in the development of memory loss in Alzheimer’s disease. / La maladie d’Alzheimer est la forme la plus commune de démence liée au vieillissement ; elle est caractérisée par des déficits précoces d’apprentissage et de mémorisation et entraîne à terme une perte généralisée des fonctions cognitives supérieures. Alors que l’amyloïde-bêta (Aβ) et la protéine tau sont traditionnellement associées au développement de la maladie d’Alzheimer, des études récentes suggèrent que d’autres facteurs, tels que le domaine intracellulaire (APP-ICD) du précurseur de la protéine amyloïde (APP), pourraient jouer un rôle. Dans notre étude, nous avons testé si l’APP-ICD pourrait affecter les mécanismes de transmission ou de plasticité synaptique dans l’hippocampe, qui sous-tendent les processus d’apprentissage et de mémorisation. Nos résultats ont indiqué que la surexpression de l’APP-ICD dans des neurones du CA1 de l’hippocampe entraînait une diminution de la transmission synaptique dépendante des récepteurs AMPA et NMDA. Notre étude a montré que cet effet était spécifique de l’APP-ICD puisque son plus proche homologue l’APLP2-ICD n’a pas eu cet effet. De plus, l’APP-ICD entraînait un blocage de la potentialisation à long terme (LTP), une augmentation de l’expression et une facilitation de l’induction de la dépression à long terme (LTD), mais l’APLP2-ICD n’a eu aucun de ces effets. Notre étude a montré que cette différence observée en transmission et en plasticité synaptique entre les deux peptides réside dans le changement d’une seule alanine dans l’APP-ICD pour une proline dans l’APLP2-ICD, et que l’APP(PAV)-ICD n’avait pas d’effet sur la plasticité synaptique. Nous avons aussi démontré que l’APLP2(AAV)-ICD mimait l’effet de l’APP-ICD pour la facilitation de la LTD. Ensuite nous avons montré que la longue forme APP-APLP2-APP (APP avec un changement de la séquence de l’Aβ pour celle homologue de l’APLP2) ne montrait pas d’effet en comparaison avec l’APP-ICD, ni sur la transmission synaptique ni sur la plasticité synaptique. Cependant, en activant le clivage par les caspases préalablement à l’induction de la LTD ou la LTP, nous avons observé une facilitation de la LTD et un iii blocage de la LTP avec l’APP-APLP2-APP, des effets que nous n’avons pas reproduit avec la longue forme APLP2. La thréonine 668 phosphorylable se trouve immédiatement après l’alanine et le site de clivage par les caspases dans l’APP-APLP2-APP. La mutation de la Thr668 pour une alanine a aboli son effet sur la LTD et restauré la LTP. Finalement, nous avons montré que la facilitation de la LTD par l’APP-APLP2-APP dépendait de la libération de calcium intracellulaire par les récepteurs ryanodines. En conséquence, nous proposons l’émergence d’un nouveau domaine de l’APP jouant un rôle critique, en plus de l’Aβ, dans les processus à la base de l’apprentissage et qui en conséquence pourrait jouer un rôle dans le développement de la maladie d’Alzheimer.