RESUMEN
The hippocampus is essential for different forms of declarative memory, including social memory, the ability to recognize and remember a conspecific. Although recent studies identify the importance of the dorsal CA2 region of the hippocampus in social memory storage, little is known about its sources of social information. Because CA2, like other hippocampal regions, receives its major source of spatial and non-spatial information from the medial and lateral subdivisions of entorhinal cortex (MEC and LEC), respectively, we investigated the importance of these inputs for social memory. Whereas MEC inputs to CA2 are dispensable, the direct inputs to CA2 from LEC are both selectively activated during social exploration and required for social memory. This selective behavioral role of LEC is reflected in the stronger excitatory drive it provides to CA2 compared with MEC. Thus, a direct LEC â CA2 circuit is tuned to convey social information that is critical for social memory.
Asunto(s)
Corteza Entorrinal , Hipocampo , Recuerdo MentalRESUMEN
The capacity to distinguish comparable experiences is fundamental for the recall of similar memories and has been proposed to require pattern separation in the dentate gyrus (DG). However, the cellular mechanisms by which mature granule cells (GCs) of the DG accomplish this function are poorly characterized. Here, we show that Kv4.2 channels selectively modulate the excitability of medial dendrites of dentate GCs. These dendrites are targeted by the medial entorhinal cortex, the main source of spatial inputs to the DG. Accordingly, we found that the spatial pattern separation capability of animals lacking the Kv4.2 channel is significantly impaired. This points to the role of intrinsic excitability in supporting the mnemonic function of the dentate and to the Kv4.2 channel as a candidate substrate promoting spatial pattern separation.
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Amphisomes are organelles of the autophagy pathway that result from the fusion of autophagosomes with late endosomes. While biogenesis of autophagosomes and late endosomes occurs continuously at axon terminals, non-degradative roles of autophagy at boutons are barely described. Here, we show that in neurons BDNF/TrkB traffick in amphisomes that signal locally at presynaptic boutons during retrograde transport to the soma. This is orchestrated by the Rap GTPase-activating (RapGAP) protein SIPA1L2, which connects TrkB amphisomes to a dynein motor. The autophagosomal protein LC3 regulates RapGAP activity of SIPA1L2 and controls retrograde trafficking and local signaling of TrkB. Following induction of presynaptic plasticity, amphisomes dissociate from dynein at boutons enabling local signaling and promoting transmitter release. Accordingly, sipa1l2 knockout mice show impaired BDNF-dependent presynaptic plasticity. Taken together, the data suggest that in hippocampal neurons, TrkB-signaling endosomes are in fact amphisomes that during retrograde transport have local signaling capacity in the context of presynaptic plasticity.
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Autofagosomas/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Endosomas/metabolismo , Proteínas Activadoras de GTPasa/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Plasticidad Neuronal/genética , Neuronas/metabolismo , Terminales Presinápticos/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Animales , Transporte Axonal , Axones/metabolismo , Dineínas/metabolismo , Proteínas Activadoras de GTPasa/genética , Hipocampo , Ratones , Ratones Noqueados , Transporte de ProteínasRESUMEN
Microtubule severing regulates cytoskeletal rearrangement underlying various cellular functions. Katanin, a heterodimer, consisting of catalytic (p60) and regulatory (p80) subunits severs dynamic microtubules to modulate several stages of cell division. The role of p60 katanin in the mammalian brain with respect to embryonic and adult neurogenesis is poorly understood. Here, we generated a Katna1 knockout mouse and found that consistent with a critical role of katanin in mitosis, constitutive homozygous Katna1 depletion is lethal. Katanin p60 haploinsufficiency induced an accumulation of neuronal progenitors in the subventricular zone during corticogenesis, and impaired their proliferation in the adult hippocampus dentate gyrus (DG) subgranular zone. This did not compromise DG plasticity or spatial and contextual learning and memory tasks employed in our study, consistent with the interpretation that adult neurogenesis may be associated with selective forms of hippocampal-dependent cognitive processes. Our data identify a critical role for the microtubule-severing protein katanin p60 in regulating neuronal progenitor proliferation in vivo during embryonic development and adult neurogenesis.
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Diferenciación Celular , Katanina/genética , Microtúbulos/metabolismo , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Neurogénesis , Factores de Edad , Alelos , Animales , Diferenciación Celular/genética , Proliferación Celular , Corteza Cerebral/embriología , Corteza Cerebral/metabolismo , Giro Dentado/embriología , Giro Dentado/metabolismo , Marcación de Gen , Haploinsuficiencia , Katanina/metabolismo , Aprendizaje , Memoria , Ratones , Ratones Noqueados , Neurogénesis/genética , Neuronas/citología , Neuronas/metabolismo , Organogénesis , FenotipoRESUMEN
Mature granule cells are poorly excitable neurons that were recently shown to fire action potentials, preferentially in bursts. It is believed that the particularly pronounced short-term facilitation of mossy fiber synapses makes granule cell bursting a very effective means of properly transferring information to CA3. However, the mechanism underlying the unique bursting behavior of mature granule cells is currently unknown. Here, we show that Cav3.2 T-type channels at the axon initial segment are responsible for burst firing of mature granule cells in rats and mice. Accordingly, Cav3.2 knockout mice fire tonic spikes and exhibit impaired bursting, synaptic plasticity and dentate-to-CA3 communication. The data show that Cav3.2 channels are strong modulators of bursting and can be considered a critical molecular switch that enables effective information transfer from mature granule cells to the CA3 pyramids.
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Potenciales de Acción/genética , Canales de Calcio Tipo T/deficiencia , Giro Dentado/citología , Neuronas/fisiología , Animales , Biofisica , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/genética , Estimulación Eléctrica , Potenciales Evocados/efectos de los fármacos , Potenciales Evocados/genética , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neurotransmisores/farmacología , Técnicas de Placa-Clamp , Vía Perforante/fisiología , Ratas , Ratas Wistar , Potenciales Sinápticos/efectos de los fármacos , Potenciales Sinápticos/genéticaRESUMEN
Compartmentalization of calcium-dependent plasticity allows for rapid actin remodeling in dendritic spines. However, molecular mechanisms for the spatio-temporal regulation of filamentous actin (F-actin) dynamics by spinous Ca2+-transients are still poorly defined. We show that the postsynaptic Ca2+ sensor caldendrin orchestrates nano-domain actin dynamics that are essential for actin remodeling in the early phase of long-term potentiation (LTP). Steep elevation in spinous [Ca2+]i disrupts an intramolecular interaction of caldendrin and allows cortactin binding. The fast on and slow off rate of this interaction keeps cortactin in an active conformation, and protects F-actin at the spine base against cofilin-induced severing. Caldendrin gene knockout results in higher synaptic actin turnover, altered nanoscale organization of spinous F-actin, defects in structural spine plasticity, LTP, and hippocampus-dependent learning. Collectively, the data indicate that caldendrin-cortactin directly couple [Ca2+]i to preserve a minimal F-actin pool that is required for actin remodeling in the early phase of LTP.
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Señalización del Calcio/fisiología , Proteínas de Unión al Calcio/deficiencia , Espinas Dendríticas/metabolismo , Potenciación a Largo Plazo/fisiología , Potenciales Sinápticos/fisiología , Animales , Células COS , Proteínas de Unión al Calcio/genética , Células Cultivadas , Chlorocebus aethiops , Espinas Dendríticas/química , Espinas Dendríticas/genética , Células HEK293 , Hipocampo/química , Hipocampo/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Técnicas de Cultivo de Órganos , Ratas , Ratas WistarRESUMEN
Neurons are highly polarized cells with apparent functional and morphological differences between dendrites and axon. A critical determinant for the molecular and functional identity of axonal and dendritic segments is the restricted expression of voltage-gated ion channels (VGCs). Several studies show an uneven distribution of ion channels and their differential regulation within dendrites and axons, which is a prerequisite for an appropriate integration of synaptic inputs and the generation of adequate action potential (AP) firing patterns. This review article will focus on the signaling pathways leading to segmented expression of voltage-gated potassium and sodium ion channels at the neuronal plasma membrane and the regulatory mechanisms ensuring segregated functions. We will also discuss the relevance of proper ion channel targeting for neuronal physiology and how alterations in polarized distribution contribute to neuronal pathology.
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Elevated c-Jun levels result in apoptosis and are evident in neurodegenerative disorders such as Alzheimer's disease and dementia and after global cerebral insults including stroke and epilepsy. NMDA receptor (NMDAR) antagonists block c-Jun upregulation and prevent neuronal cell death following excitotoxic insults. However, the molecular mechanisms regulating c-Jun abundance in neurons are poorly understood. Here, we show that the synaptic component Proline rich 7 (PRR7) accumulates in the nucleus of hippocampal neurons following NMDAR activity. We find that PRR7 inhibits the ubiquitination of c-Jun by E3 ligase SCF(FBW) (7) (FBW7), increases c-Jun-dependent transcriptional activity, and promotes neuronal death. Microarray assays show that PRR7 abundance is directly correlated with transcripts associated with cellular viability. Moreover, PRR7 knockdown attenuates NMDAR-mediated excitotoxicity in neuronal cultures in a c-Jun-dependent manner. Our results show that PRR7 links NMDAR activity to c-Jun function and provide new insights into the molecular processes that underlie NMDAR-dependent excitotoxicity.
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Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Proteínas de la Membrana/metabolismo , Neuronas/fisiología , Procesamiento Proteico-Postraduccional , Animales , Supervivencia Celular , Células Cultivadas , Agonistas de Aminoácidos Excitadores/metabolismo , Hipocampo/patología , Humanos , Análisis por Micromatrices , N-Metilaspartato/metabolismo , Ratas , UbiquitinaciónRESUMEN
Jacob, the protein encoded by the Nsmf gene, is involved in synapto-nuclear signaling and docks an N-Methyl-D-Aspartate receptor (NMDAR)-derived signalosome to nuclear target sites like the transcription factor cAMP-response-element-binding protein (CREB). Several reports indicate that mutations in NSMF are related to Kallmann syndrome (KS), a neurodevelopmental disorder characterized by idiopathic hypogonadotropic hypogonadism (IHH) associated with anosmia or hyposmia. It has also been reported that a protein knockdown results in migration deficits of Gonadotropin-releasing hormone (GnRH) positive neurons from the olfactory bulb to the hypothalamus during early neuronal development. Here we show that mice that are constitutively deficient for the Nsmf gene do not present phenotypic characteristics related to KS. Instead, these mice exhibit hippocampal dysplasia with a reduced number of synapses and simplification of dendrites, reduced hippocampal long-term potentiation (LTP) at CA1 synapses and deficits in hippocampus-dependent learning. Brain-derived neurotrophic factor (BDNF) activation of CREB-activated gene expression plays a documented role in hippocampal CA1 synapse and dendrite formation. We found that BDNF induces the nuclear translocation of Jacob in an NMDAR-dependent manner in early development, which results in increased phosphorylation of CREB and enhanced CREB-dependent Bdnf gene transcription. Nsmf knockout (ko) mice show reduced hippocampal Bdnf mRNA and protein levels as well as reduced pCREB levels during dendritogenesis. Moreover, BDNF application can rescue the morphological deficits in hippocampal pyramidal neurons devoid of Jacob. Taken together, the data suggest that the absence of Jacob in early development interrupts a positive feedback loop between BDNF signaling, subsequent nuclear import of Jacob, activation of CREB and enhanced Bdnf gene transcription, ultimately leading to hippocampal dysplasia.
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Factor Neurotrófico Derivado del Encéfalo/genética , Dendritas/metabolismo , Hipocampo/crecimiento & desarrollo , Proteínas del Tejido Nervioso/genética , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Regulación del Desarrollo de la Expresión Génica , Hormona Liberadora de Gonadotropina/metabolismo , Hipocampo/metabolismo , Ratones , Ratones Noqueados , Neuronas/metabolismo , Fosforilación , ARN Mensajero/biosíntesis , Transducción de Señal , Sinapsis/genética , Sinapsis/metabolismoRESUMEN
The dentate gyrus is the main entrance of highly processed information to the hippocampus which derives from associative cortices and it is one of the few privileged areas in the brain where adult neurogenesis occurs. This creates the unique situation that neurons of diverse maturation stages are part of one neuronal network at any given point in life. While recently adult-born cells have a low induction threshold for long-term potentiation several studies suggest that following maturation granule cells are poorly excitable and they exhibit reduced Hebbian synaptic plasticity to an extent that it was even suggested that they functionally retire. Here, we review the functional properties of mature granule cells and discuss how plasticity of intrinsic excitability and alterations in excitation-inhibition balance might impact on their role in hippocampal information processing.
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Hipocampo/fisiología , Neuronas/fisiología , Animales , Humanos , Plasticidad Neuronal/fisiologíaRESUMEN
The dentate gyrus is the main entry gate for cortical input to the hippocampus and one of the few brain areas where adult neurogenesis occurs. Several studies have shown that it is relatively difficult to induce synaptic plasticity in mature but not in newborn dentate granule cells. In the present work we have systematically addressed how classical protocols to induce synaptic plasticity affect action potential firing and intrinsic excitability in mature granule cells. We found that stimulation paradigms considered to be relevant for learning processes consistently modified the probability to generate action potentials in response to a given synaptic input in mature cells, in some paradigms even without any modification of synaptic strength. Collectively the results suggest that plasticity of intrinsic dendritic excitability has a lower induction-threshold than synaptic plasticity in mature granule cells and that this form of plasticity might be an important mechanism by which mature granule cells contribute to hippocampal function.