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Understanding the intricate mechanisms underlying memory formation and retention relies on unraveling how the hippocampus, a structure fundamental for memory acquisition, is organized. Within the complex hippocampal network, interneurons play a crucial role in orchestrating memory processes. Among these interneurons, Oriens-Lacunosum Moleculare (OLM) cells emerge as key regulators, governing the flow of information to CA1 pyramidal cells. In this review, we explore OLM interneurons in detail, describing their mechanisms and effects on memory processing, particularly in spatial and contextual memory tasks. Our aim is to provide a detailed understanding of how OLM interneurons contribute to the dynamic landscape of memory formation and retrieval.
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Numerous studies have shown that aging in humans leads to a decline in olfactory function, resulting in deficits in acuity, detection threshold, discrimination, and olfactory-associated memories. Furthermore, impaired olfaction has been identified as a potential indicator for the onset of age-related neurodegenerative diseases, including Alzheimer's disease (AD). Studies conducted on mouse models of AD have largely mirrored the findings in humans, thus providing a valuable system to investigate the cellular and circuit adaptations of the olfactory system during natural and pathological aging. However, the majority of previous research has focused on assessing the detection of neutral or synthetic odors, with little attention given to the impact of aging and neurodegeneration on the recognition of social cues-a critical feature for the survival of mammalian species. Therefore, in this study, we present a battery of olfactory tests that use conspecific urine samples to examine the changes in social odor recognition in a mouse model of neurodegeneration.
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Doença de Alzheimer , Transtornos do Olfato , Humanos , Camundongos , Animais , Sinais (Psicologia) , Olfato , Transtornos do Olfato/diagnóstico , Comportamento Social , Modelos Animais de Doenças , MamíferosRESUMO
Normal aging and many age-related disorders such as Alzheimer's disease cause deficits in olfaction; however, it is currently unknown how natural and pathological aging impacts the detection of social odors which might contribute to the impoverishment of social behavior at old age further worsening overall health. Analysis of the vomeronasal organ, the main gateway to pheromone-encoded information, indicated that natural and pathological aging distinctively affects the neurogenic ability of the vomeronasal sensory epithelium. Whereas cell proliferation remained majorly preserved in 1-year-old APP/PS1 mice, naturally aged animals exhibited significant deficiencies in the number of mature, proliferative, and progenitor cells. These alterations may support age-related deficits in the recognition of social cues and the display of social behavior. Our findings indicate that aging disrupts the processing of social olfactory cues decreasing social odor exploration, discrimination, and habituation in both wild-type senescent (2-year-old) mice and in 1-year-old double mutant model of Alzheimer's disease (APP/PS1). Furthermore, social novelty was diminished in 1-year-old APP/PS1 mice, indicating that alterations in the processing of social cues are accelerated during pathological aging. This study reveals fundamental differences in the cellular processes by which natural and pathological aging disrupts the exploration of social information and social behavior.
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Doença de Alzheimer , Camundongos , Animais , Doença de Alzheimer/patologia , Feromônios , Comportamento Social , Olfato , Envelhecimento/patologia , Camundongos Transgênicos , Precursor de Proteína beta-Amiloide , Modelos Animais de DoençasRESUMO
AMPA receptors (AMPARs) are critical for mediating glutamatergic synaptic transmission and plasticity, thus playing a major role in the molecular machinery underlying cellular substrates of memory and learning. Their expression pattern, transport and regulatory mechanisms have been extensively studied in the hippocampus, but their functional properties in other brain regions remain poorly understood. Interestingly, electrophysiological and molecular evidence has confirmed a prominent role of AMPARs in the regulation of hypothalamic function. This review summarizes the existing evidence on AMPAR-mediated transmission in the hypothalamus, where they are believed to orchestrate the role of glutamatergic transmission in autonomous, neuroendocrine function, body homeostasis, and social behavior.
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Oxytocin (OXT) and arginine vasopressin (AVP) support a broad range of behaviors and homeostatic functions including sex-specific and context-appropriate social behaviors. Although the alterations of these systems have been linked with social-related disorders such as autism spectrum disorder, their formation and developmental dynamics remain largely unknown. Using novel brain clearing techniques and 3D imaging, we have reconstructed the specification of oxytocinergic and vasopressinergic circuits in the developing mouse brain with unprecedented cellular resolution. A systematic quantification indicates that OXT and AVP neurons in the hypothalamus display distinctive developmental dynamics and high cellular plasticity from embryonic to early postnatal stages. Our findings reveal new insights into the specification and consolidation of neuropeptidergic systems in the developing CNS.
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Encéfalo/citologia , Encéfalo/metabolismo , Hipotálamo/metabolismo , Vias Neurais , Ocitocina/metabolismo , Vasopressinas/metabolismo , Animais , Feminino , Hipotálamo/citologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Comportamento SocialRESUMO
It is well--established that Rab11-dependent recycling endosomes drive the activity-dependent delivery of AMPA receptors (AMPARs) into synapses during long-term potentiation (LTP). Nevertheless, the molecular basis for this specialized function of recycling endosomes is still unknown. Here, we have investigated RAB11FIP2 (FIP2 hereafter) as a potential effector of Rab11-dependent trafficking during LTP in rat hippocampal slices. Surprisingly, we found that FIP2 operates independently from Rab11 proteins, and acts as a negative regulator of AMPAR synaptic trafficking. Under basal conditions, FIP2 associates with AMPARs at immobile compartments, separately from recycling endosomes. Using shRNA-mediated knockdown, we found that FIP2 prevents GluA1 (encoded by the Gria1 gene) AMPARs from reaching the surface of dendritic spines in the absence of neuronal stimulation. Upon induction of LTP, FIP2 is rapidly mobilized, dissociates from AMPARs and undergoes dephosphorylation. Interestingly, this dissociation of the FIP2-AMPAR complex, together with FIP2 dephosphorylation, is required for LTP, but the interaction between FIP2 and Rab11 proteins is not. Based on these results, we propose a retention-release mechanism, where FIP2 acts as a gate that restricts the trafficking of AMPARs, until LTP induction triggers their release and allows synaptic delivery.
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Proteínas de Transporte/metabolismo , Espinhas Dendríticas/metabolismo , Potenciação de Longa Duração/fisiologia , Proteínas de Membrana/metabolismo , Receptores de AMPA/metabolismo , Sinapses/metabolismo , Animais , Proteínas de Transporte/genética , Endossomos/metabolismo , Feminino , Hipocampo/metabolismo , Masculino , Proteínas de Membrana/genética , Ratos , Ratos Wistar , Receptores de AMPA/genéticaRESUMO
Soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) proteins mediate membrane fusion events in eukaryotic cells. Traditionally recognized as major players in regulating presynaptic neurotransmitter release, accumulative evidence over recent years has identified several SNARE proteins implicated in important postsynaptic processes such as neurotransmitter receptor trafficking and synaptic plasticity. Here we analyze the emerging data revealing this novel functional dimension for SNAREs with a focus on the molecular specialization of vesicular recycling and fusion in dendrites compared to those at axon terminals and its impact in synaptic transmission and plasticity.
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Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Proteínas SNARE/metabolismo , Transmissão Sináptica/fisiologia , Animais , HumanosRESUMO
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) enable most excitatory transmission in the brain and are crucial for mediating basal synaptic strength and plasticity. Because of the importance of their function, AMPAR dynamics, activity and subunit composition undergo a tight regulation which begins as early as prenatal development and continues through adulthood. Accumulating evidence suggests that the precise regulatory mechanisms involved in orchestrating AMPAR trafficking are challenged in the aging brain. In turn dysregulation of AMPARs can be linked to most neurological and neurodegenerative disorders. Understanding the mechanisms that govern AMPAR signaling during natural and pathological cognitive decline will guide the efforts to develop most effective ways to tackle neurodegenerative diseases which are one of the primary burdens afflicting an increasingly aging population. In this review, I provide a brief overview of the molecular mechanisms involved in AMPAR trafficking highlighting what is currently known about how these processes change with age and disease. As a particularly well-studied example of AMPAR dysfunction in pathological aging I focus in Alzheimer's disease (AD) with special emphasis in how the production of neurofibrillary tangles (NFTs) and amyloid-ß plaques may contribute to disruption in AMPAR function.
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Hippocampal interneurons comprise a diverse family of inhibitory neurons that are critical for detailed information processing. Along with gamma-aminobutyric acid (GABA), interneurons secrete a myriad of neuroactive substances via secretory vesicles but the molecular composition and regulatory mechanisms remain largely unknown. In this study, we have carried out an immunohistofluorescence analysis to describe the molecular content of vesicles in distinct populations of hippocampal neurons. Our results indicate that phogrin, an integral protein of secretory vesicles in neuroendocrine cells, is highly enriched in parvalbumin-positive interneurons. Consistently, immunoelectron microscopy revealed phogrin staining in axon terminals of symmetrical synapses establishing inhibitory contacts with cell bodies of CA1 pyramidal neurons. Furthermore, phogrin is highly expressed in CA3 and dentate gyrus (DG) interneurons which are both positive for PV and neuropeptide Y. Surprisingly, chromogranin B a canonical large dense core vesicle marker, is excluded from inhibitory cells in the hippocampus but highly expressed in excitatory CA3 pyramidal neurons and DG granule cells. Our results provide the first evidence of phogrin expression in hippocampal interneurons and suggest the existence of molecularly distinct populations of secretory vesicles in different types of inhibitory neurons.
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Postsynaptic AMPA-type glutamate receptors (AMPARs) are among the major determinants of synaptic strength and can be trafficked into and out of synapses. Neuronal activity regulates AMPAR trafficking during synaptic plasticity to induce long-term changes in synaptic strength, including long-term potentiation (LTP) and long-term depression (LTD). Rab family GTPases regulate most membrane trafficking in eukaryotic cells; particularly, Rab11 and its effectors are implicated in mediating postsynaptic AMPAR insertion during LTP. To explore the synaptic function of Rab11Fip5, a neuronal Rab11 effector and a candidate autism-spectrum disorder gene, we performed shRNA-mediated knock-down and genetic knock-out (KO) studies. Surprisingly, we observed robust shRNA-induced synaptic phenotypes that were rescued by a Rab11Fip5 cDNA but that were nevertheless not observed in conditional KO neurons. Both in cultured neurons and acute slices, KO of Rab11Fip5 had no significant effect on basic parameters of synaptic transmission, indicating that Rab11Fip5 is not required for fundamental synaptic operations, such as neurotransmitter release or postsynaptic AMPAR insertion. KO of Rab11Fip5 did, however, abolish hippocampal LTD as measured both in acute slices or using a chemical LTD protocol in cultured neurons but did not affect hippocampal LTP. The Rab11Fip5 KO mice performed normally in several behavioral tasks, including fear conditioning, but showed enhanced contextual fear extinction. These are the first findings to suggest a requirement for Rab11Fip5, and presumably Rab11, during LTD.
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Proteínas de Transporte/metabolismo , Hipocampo/citologia , Depressão Sináptica de Longo Prazo/fisiologia , Proteínas Mitocondriais/metabolismo , Sinapses/genética , Animais , Animais Recém-Nascidos , Proteínas de Transporte/genética , Condicionamento Psicológico/fisiologia , Comportamento Exploratório/fisiologia , Medo/fisiologia , Antagonistas GABAérgicos/farmacologia , Técnicas In Vitro , Depressão Sináptica de Longo Prazo/genética , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Mitocondriais/genética , Mutação/genética , Picrotoxina/farmacologia , Receptores de AMPA/metabolismo , Comportamento Social , Sinapses/fisiologia , Proteínas rab de Ligação ao GTPRESUMO
Retinoic acid (RA)-dependent homeostatic plasticity and NMDA receptor-dependent long-term potentiation (LTP), a form of Hebbian plasticity, both enhance synaptic strength by increasing the abundance of postsynaptic AMPA receptors (AMPARs). However, it is unclear whether the molecular mechanisms mediating AMPAR trafficking during homeostatic and Hebbian plasticity differ, and it is unknown how RA signaling impacts Hebbian plasticity. Here, we show that RA increases postsynaptic AMPAR abundance using an activity-dependent mechanism that requires a unique SNARE (soluble NSF-attachment protein receptor)-dependent fusion machinery different from that mediating LTP. Specifically, RA-induced AMPAR trafficking did not involve complexin, which activates SNARE complexes containing syntaxin-1 or -3, but not complexes containing syntaxin-4, whereas LTP required complexin. Moreover, RA-induced AMPAR trafficking utilized the Q-SNARE syntaxin-4, whereas LTP utilized syntaxin-3; both additionally required the Q-SNARE SNAP-47 and the R-SNARE synatobrevin-2. Finally, acute RA treatment blocked subsequent LTP expression, probably by increasing AMPAR trafficking. Thus, RA-induced homeostatic plasticity involves a novel, activity-dependent postsynaptic AMPAR-trafficking pathway mediated by a unique SNARE-dependent fusion machinery.
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Exocitose/fisiologia , Potenciação de Longa Duração/fisiologia , Receptores de AMPA/efeitos dos fármacos , Receptores de AMPA/metabolismo , Proteínas SNARE/metabolismo , Tretinoína/farmacologia , Animais , Sinergismo Farmacológico , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Homeostase/fisiologia , Camundongos , Plasticidade Neuronal/fisiologia , Técnicas de Cultura de Órgãos , Transporte Proteico/fisiologia , Proteínas Qa-SNARE/metabolismo , Sinapses/metabolismo , Potenciais Sinápticos/fisiologiaRESUMO
Each year, 10 million people worldwide survive the neurologic injury associated with a stroke. Importantly, stroke survivors have more than twice the risk of subsequently developing dementia compared with people who have never had a stroke. The link between stroke and the later development of dementia is not understood. There are reports of oligoclonal bands in the CSF of stroke patients, suggesting that in some people a B-lymphocyte response to stroke may occur in the CNS. Therefore, we tested the hypothesis that a B-lymphocyte response to stroke could contribute to the onset of dementia. We discovered that, in mouse models, activated B-lymphocytes infiltrate infarcted tissue in the weeks after stroke. B-lymphocytes undergo isotype switching, and IgM, IgG, and IgA antibodies are found in the neuropil adjacent to the lesion. Concurrently, mice develop delayed deficits in LTP and cognition. Genetic deficiency, and the pharmacologic ablation of B-lymphocytes using an anti-CD20 antibody, prevents the appearance of delayed cognitive deficits. Furthermore, immunostaining of human postmortem tissue revealed that a B-lymphocyte response to stroke also occurs in the brain of some people with stroke and dementia. These data suggest that some stroke patients may develop a B-lymphocyte response to stroke that contributes to dementia, and is potentially treatable with FDA-approved drugs that target B cells.
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Subpopulações de Linfócitos B/imunologia , Demência/etiologia , Infarto da Artéria Cerebral Média/imunologia , Idoso , Animais , Estudos de Casos e Controles , Demência/imunologia , Demência/fisiopatologia , Feminino , Humanos , Imunoglobulinas/imunologia , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/fisiopatologia , Potenciação de Longa Duração , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BLRESUMO
Several symptoms associated with chronic pain, including fatigue and depression, are characterized by reduced motivation to initiate or complete goal-directed tasks. However, it is unknown whether maladaptive modifications in neural circuits that regulate motivation occur during chronic pain. Here, we demonstrate that the decreased motivation elicited in mice by two different models of chronic pain requires a galanin receptor 1-triggered depression of excitatory synaptic transmission in indirect pathway nucleus accumbens medium spiny neurons. These results demonstrate a previously unknown pathological adaption in a key node of motivational neural circuitry that is required for one of the major sequela of chronic pain states and syndromes.
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Dor Crônica/fisiopatologia , Dor Crônica/psicologia , Depressão Sináptica de Longo Prazo/fisiologia , Motivação , Núcleo Accumbens/fisiopatologia , Receptor Tipo 1 de Galanina/fisiologia , Animais , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor Tipo 1 de Galanina/antagonistas & inibidores , Receptor Tipo 1 de Galanina/genéticaRESUMO
Sorting endosomes carry α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) from their maturation sites to their final destination at the dendritic plasma membrane through both constitutive and regulated exocytosis. Insertion of functional AMPARs into the postsynaptic membrane is essential for maintaining fast excitatory synaptic transmission and plasticity. Despite this crucial role in neuronal function, the machinery mediating the fusion of AMPAR-containing endosomes in dendrites has been largely understudied in comparison to presynaptic vesicle exocytosis. Increasing evidence suggests that similarly to neurotransmitter release, AMPARs insertion relies on the formation of a SNARE complex (soluble NSF-attachment protein receptor), whose composition in dendrites has just begun to be elucidated. This review analyzes recent findings of the fusion machinery involved in regulated AMPARs insertion and discusses how dendritic exocytosis and AMPARs lateral diffusion may work together to support synaptic plasticity.
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Membrane fusion during exocytosis is mediated by assemblies of SNARE (soluble NSF-attachment protein receptor) and SM (Sec1/Munc18-like) proteins. The SNARE/SM proteins involved in vesicle fusion during neurotransmitter release are well understood, whereas little is known about the protein machinery that mediates activity-dependent AMPA receptor (AMPAR) exocytosis during long-term potentiation (LTP). Using direct measurements of LTP in acute hippocampal slices and an in vitro LTP model of stimulated AMPAR exocytosis, we demonstrate that the Q-SNARE proteins syntaxin-3 and SNAP-47 are required for regulated AMPAR exocytosis during LTP but not for constitutive basal AMPAR exocytosis. In contrast, the R-SNARE protein synaptobrevin-2/VAMP2 contributes to both regulated and constitutive AMPAR exocytosis. Both the central complexin-binding and the N-terminal Munc18-binding sites of syntaxin-3 are essential for its postsynaptic role in LTP. Thus, postsynaptic exocytosis of AMPARs during LTP is mediated by a unique fusion machinery that is distinct from that used during presynaptic neurotransmitter release.
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Exocitose/fisiologia , Potenciação de Longa Duração/fisiologia , Fusão de Membrana/fisiologia , Neurônios/fisiologia , Proteínas SNARE/metabolismo , Animais , Animais Recém-Nascidos , Biofísica , Células Cultivadas , Estimulação Elétrica , Antagonistas de Aminoácidos Excitatórios/farmacologia , Exocitose/efeitos dos fármacos , Técnicas de Transferência de Genes , Glicina/farmacologia , Hipocampo/citologia , Técnicas In Vitro , Potenciação de Longa Duração/efeitos dos fármacos , Fusão de Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Proteínas Qa-SNARE/metabolismo , Quinoxalinas/farmacologia , Receptores de AMPA/metabolismo , Receptores da Transferrina/metabolismo , Proteínas SNARE/genética , Sintaxina 1/metabolismo , Proteína 2 Associada à Membrana da Vesícula/metabolismo , Proteínas de Transporte Vesicular/metabolismoRESUMO
Objetivo: describir el comportamiento demográfico y clínico de los pacientes traumatizados de una institución de cuarto nivel de complejidad que ingresaron entre el 2005 y el 2008. Metodología: estudio descriptivo retrospectivo basado en información de pacientes que ingresaron a urgencias y hospitalización. Se estimaron frecuencias y porcentajes para las variables demográficas y algunas clínicas. Finalmente, se realizó un muestreo aleatorio simple para estimar la puntuación de gravedad de las lesiones (trauma and injury severity score-triss). Resultados: en este período ingresaron 165736 pacientes, de ellos, 57382 correspondieron a ingresos por trauma (35% del total). El sexo masculino y el grupo de edad de 20-29 años fueron los más afectados. La causa de ingreso predominante fue la de accidentes de tránsito, seguida por otros tipos de accidentes (caídas, quemaduras, ahogamientos). Fueron hospitalizados 6721 pacientes, de los cuales fallecieron 278, con tasa de mortalidad global de 4,1. La parte del cuerpo más afectada en estos pacientes fueron las extremidades (42%) y los traumas en cabeza y cuello (19%). Para estimar la triss, se analizaron en total 347 pacientes. El índice de severidad del trauma (iss) calculado fue mayor de 49 en 3,17% de los pacientes analizados. La escala revisada de trauma (rts) promedio fue de 7507. Las cifras de presión arterial sistólica y frecuencia respiratoria presentaron una media de 121,948 mmHg y 18,659 min respectivamente, y en la escala de coma de Glasgow, 30 pacientes obtuvieron un puntaje menor o igual a 8. El total de muertes esperadas correspondió a 17 pacientes y el total de muertes observadas a 19. Finalmente, la triss calculada fue de 1,097...
Objective: to describe the demographic and clinical behavior of trauma inpatients admitted in an institution of fourth level of complexity between 2005 and 2008. Methodology: descriptive and retrospective study based on information from patients admitted to the emergency room and to stay hospitalized. Frequencies and percentages for both demographic and inical variables were estimated. Finally, a simple random sampling was conducted to estimate the trauma and injury severity score (triss). Results: during this period a total amount of 165736 inpatients were admitted; 57382 of them were admitted for trauma (35% Perfil demográfico y clínico de pacientes traumatizados: en una institución de cuarto nivel. Medellín 2005-2008 Facultad Nacional de Salud Pública 243 of the total). The male gender and the 20-29 years of age groups were the most affected by trauma. The predominant cause of admission was traffic accidents followed by other types of accidents (falls, burns, drowning). 6721 patients were hospitalized, 278 of which died while the general mortality rate was 4,1. The most affected body part in those patients was the body limbs (42%) and trauma to the head and neck (19%). In order to estimate the triss, a total amount of 347 patients we analyzed. The estimated triss scored more than 49 for 3,17% of the patients studied, the average was 7,507 rts, the systolic blood pressure and the respiratory rate showed an average of 121,948 mmHg and 18,659 minutes respectively, and according to the Glasgow coma scale, 30 patients scored less than or equal to 8. The total amount of expected deaths was 17 patients and the total amount of observed deaths was 19. Finally, the triss calculated was 1.097...
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Escala de Coma de Glasgow , Mortalidade , Ferimentos e LesõesRESUMO
AKAP79/150 is a protein scaffold that is thought to position specific kinases (protein kinase A and C) and phosphatases (calcineurin) in appropriate synaptic domains so that their activities can regulate excitatory synaptic strength. Using a viral-mediated molecular replacement strategy in rat hippocampal slices, we found that AKAP is required for NMDA receptor-dependent long-term depression solely because of its interaction with calcineurin.
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Proteínas de Ancoragem à Quinase A/metabolismo , Calcineurina/metabolismo , Depressão Sináptica de Longo Prazo/fisiologia , Neurônios/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Proteínas de Ancoragem à Quinase A/genética , Animais , Região CA1 Hipocampal/fisiologia , Células Cultivadas , Potenciais Pós-Sinápticos Excitadores/fisiologia , Técnicas In Vitro , Células Piramidais/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Transmissão Sináptica/fisiologiaRESUMO
Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is an important regulator of phosphatidylinositol-(3,4,5,)-trisphosphate signalling, which controls cell growth and differentiation. However, PTEN is also highly expressed in the adult brain, in which it can be found in dendritic spines in hippocampus and other brain regions. Here, we have investigated specific functions of PTEN in the regulation of synaptic function in excitatory hippocampal synapses. We found that NMDA receptor activation triggers a PDZ-dependent association between PTEN and the synaptic scaffolding molecule PSD-95. This association is accompanied by PTEN localization at the postsynaptic density and anchoring within the spine. On the other hand, enhancement of PTEN lipid phosphatase activity is able to drive depression of AMPA receptor-mediated synaptic responses. This activity is specifically required for NMDA receptor-dependent long-term depression (LTD), but not for LTP or metabotropic glutamate receptor-dependent LTD. Therefore, these results reveal PTEN as a regulated signalling molecule at the synapse, which is recruited to the postsynaptic membrane upon NMDA receptor activation, and is required for the modulation of synaptic activity during plasticity.