Abstract:

Cell morphology and its interaction with the extracellular environment are integrated processes involving a number of intracellular controllers orchestrating cytoskeletal proteins and their interaction with the cell membrane and anchorage proteins. Sex steroids are effective regulators of cell morphology and tissue organisation, and recent evidence indicates that this is obtained through the regulation of the actin cytoskeleton. Intriguingly, many of these regulatory actions related to cell morphology are achieved through the rapid, nonclassical signalling of sex steroid receptors to kinase cascades, independently from nuclear alteration of gene expression or protein synthesis. The identification of the mechanistic basis for these rapid actions on cell cytoskeleton has special relevance for the characterisation of the effects of sex steroids under physiological conditions, such as for the development of neurone/neurone interconnections and dendritic spine density. This is considered to be critical for gender-specific differences in brain function and dysfunction. Recent advancements in the characterisation of the molecular basis of the extranuclear signalling of sex steroids help to clarify the role of oestrogen and progesterone in the brain, and may turn out to be of relevance for clinical purposes. This review highlights the regulatory effects of oestrogens and progesterone on actin cytoskeleton and neurone morphology, as well as recent progresses in the characterisation of these mechanisms, providing insights and working hypotheses on possible clinical applications for the modulation of these pathways in the central nervous system.

Author affiliation: Sanchez, Angel Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina

Author affiliation: Flamini, Marina Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina

Author affiliation: Polak, K.. Università degli Studi di Pisa; Italia

Author affiliation: Palla G.. Università degli Studi di Pisa; Italia

Author affiliation: Spina, S.. Università degli Studi di Pisa; Italia

Author affiliation: Mannella, P.. Università degli Studi di Pisa; Italia

Author affiliation: Genazzani, A. D.. Università degli Studi di Pisa; Italia

Author affiliation: Simoncini, T.. Università degli Studi di Pisa; Italia

Abstract:

Psychostimulant drugs of abuse increase dendritic spine density in reward centers of the brain. However, little is known about their effects in the hippocampus, where activity-dependent changes in the density of dendritic spine are associated with learning and memory. Recent reports suggest that Cdk5 plays an important role in drug addiction, but its role in psychostimulant?s effects on dendritic spines in hippocampus remain unknown. We used in vivo and in vitro approaches to demonstrate that amphetamine increases dendritic spine density in pyramidal neurons of the hippocampus. Primary cultures and organotypic slice cultures were used for cellular, molecular, pharmacological and biochemical analyses of the role of Cdk5/p25 in amphetamine-induced dendritic spine formation. Amphetamine (two-injection protocol) increased dendritic spine density in hippocampal neurons of thy1-green fluorescent protein (GFP) mice, as well as in hippocampal cultured neurons and organotypic slice cultures. Either genetic or pharmacological inhibition of Cdk5 activity prevented theamphetamine?induced increase in dendritic spine density. Amphetamine also increased spine density in neurons overexpressing the strong Cdk5 activator p25. Finally, inhibition of calpain, the protease necessary for the conversion of p35 to p25, prevented amphetamine?s effect on dendritic spine density. We demonstrate, for the first time, that amphetamine increases the density of dendritic spine in hippocampal pyramidal neurons in vivo and in vitro. Moreover, we show that the Cdk5/p25 signaling and calpain activity are both necessary for the effect of amphetamine on dendritic spine density. The identification of molecular mechanisms underlying psychostimulant effects provides novel and promising therapeutic approaches for the treatment of drug addiction.

Author affiliation: Ferreras, Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina

Author affiliation: Fernández, Guillermo César. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina

Author affiliation: Danelon, Víctor. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentina

Author affiliation: Pisano, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina

Author affiliation: Masseroni, Maria Luján. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina

Author affiliation: Chapleau, Christopher. University of Alabama at Birmingahm; Estados Unidos

Author affiliation: Krapacher, Favio Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina

Author affiliation: Mlewski, Estela Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina

Author affiliation: Masco, Daniel Hugo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentina

Author affiliation: Arias Grandio, Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina

Author affiliation: Pozzo Miller, Lucas. University of Alabama at Birmingahm; Estados Unidos

Author affiliation: Paglini, Maria Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina

Abstract:

Perinatal asphyxia (PA) is a medical condition associated with a high short-term morbimortality and different long-term neurological diseases. In previous works, we have shown that neuronal and synaptic changes in rat striatum lead to ubi-protein accumulation in post-synaptic density (PSD) after six months of sub-severe PA. However, very little is known about the synaptic and related structural modifications induced by PA in young rats. In the present work, we studied neuronal cytoskeleton modifications in striatum induced by subsevere PA in 30-day-old rats. We observed a significant decrease in the number of neurons, in particular calbindin immunoreactive neurons after PA. In addition, it was also observed that actin cytoskeleton was highly modified in the PSD as well as an increment of F-actin staining by Phalloidin-alexa 488 in the striatum of PA rats. Using correlative fluorescence-electron microscopy photooxidation, we confirmed and extended confocal observations. F-actin staining augmentation was mostly related with an increment in the number of mushroom-shaped spines. Consistent with microscopic data, Western blot analysis revealed a β-actin increment in PSD in PA rats. On the other hand, MAP-2 immunostaining was decreased after PA, being NF-200 expression unmodified. Although neuronal death was observed, signs of generalized neurodegeneration were absent. Taken together these results showed early post-synaptic F-actin cytoskeleton changes induced by PA with slightly modifications in the other components of the neuronal cytoskeleton, suggesting that F-actin accumulation in the dendritic spines could be involved in the neuronal loss induced by PA. © 2011 Wiley Periodicals, Inc.

Author affiliation: Saraceno, Gustavo Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; Argentina

Author affiliation: Ayala, Maria Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; Argentina

Author affiliation: Badorrey, Maria Sol. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; Argentina

Author affiliation: Holubiec, Mariana Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; Argentina

Author affiliation: Romero, Juan Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; Argentina

Author affiliation: Galeano, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; Argentina

Author affiliation: Barreto, G.. Pontificia Universidad Javeriana; Colombia

Author affiliation: Giraldez Alvárez, L. D.. Universidade Federal da Bahia; Brasil

Author affiliation: Kolliker Frers, Rodolfo Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; Argentina

Author affiliation: Coirini, Hector. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina

Author affiliation: Capani, Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; Argentina

Abstract:

GABAergic signaling in the basolateral amygdala complex (BLA) plays a crucial role on the modulation of the stress influence on fear memory. Moreover, accumulating evidence suggests that the dorsal hippocampus (DH) is a downstream target of BLA neurons in contextual fear. Given that hippocampal structural plasticity is proposed to provide a substrate for the storage of long-term memories, the main aim of this study is to evaluate the modulation of GABA neurotransmission in the BLA on spine density in the DH following stress on contextual fear learning. The present findings show that prior stressful experience promoted contextual fear memory and enhanced spine density in the DH. Intra-BLA infusion of midazolam, a positive modulator of GABAa sites, prevented the facilitating influence of stress on both fear retention and hippocampal dendritic spine remodeling. Similarly to the stress-induced effects, the blockade of GABAa sites within the BLA ameliorated fear memory emergence and induced structural remodeling in the DH. These findings suggest that GABAergic transmission in BLA modulates the structural changes in DH associated to the influence of stress on fear memory.

Author affiliation: Giachero, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina

Author affiliation: Calfa, Gaston Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina

Author affiliation: Molina, Víctor Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; Argentina

Abstract:

La incidencia de los desórdenes metabólicos, incluyendo obesidad, diabetes de tipo 2 y síndrome metabólico, ha aumentando dramáticamente en las últimas décadas y emerge como un problema relevante para la salud pública de nuestro tiempo. A su vez, constituyen unos de los principales factores de riesgo para el desarrollo de desórdenes neurodegenerativos como la enfermedad de Alzheimer (EA), cuyo impacto es creciente en sociedades modernas. La resistencia a insulina y la inflamación promueven el daño cognitivo, jugando un papel crucial en el desarrollo de la EA. Sin embargo, es poco lo que se conoce acerca de las vías moleculares y celulares involucradas a nivel del sistema nervioso central. El objetivo de este trabajo de Tesis fue estudiar el impacto de una dieta moderadamente alta en grasas (HFD) sobre el sistema límbico en etapas juveniles, donde la fisiología y conectividad cerebral se encuentran en plena maduración, y los posibles mecanismos involucrados. Para ello, trabajamos con ratones macho C57BL/6J alimentados con HFD o dieta control desde el destete hasta los 2 o 5 meses de vida. La HFD provocó resistencia a insulina, inflamación periférica y central pero no obesidad. En el hipocampo se observó activación glial, disminución de la capacidad neurogénica en el giro dentado y el estudio de espinas dendríticas mostró predominio del tipo inmaduro (tipo III) en detrimento de los otros tipos. Los ratones HFD perdieron la capacidad de construir un nido, mostraron deficiencias cognitivas y alteraciones emotivas, en particular signos asemejables a la ansiedad y la depresión. Con el objetivo de profundizar el estudio de la interacción glía-neurona en el contexto de la disfunción metabólica, nos propusimos estudiar el efecto del ácido graso saturado palmitato (PA), uno de los más representados en la HFD, sobre cultivos primarios de microglía. La exposición a PA indujo un fenotipo microglial pro-inflamatorio y la liberación de vesículas extracelulares. Aislamos las microvesículas y los exosomas provenientes de ese cultivo y estudiamos su efecto sobre neuronas primarias de ratón. Los exosomas de microglía estimulada con palmitato se asociaron a un predominio de espinas inmaduras, tipo III o finas, en consonancia con los estudios in vivo. Este trabajo de Tesis muestra múltiples alteraciones en parámetros neurológicos como consecuencia de la exposición temprana a una dieta moderadamente elevada en grasas, muchas de las cuales se encuentran presentes en enfermedades tipo EA. A partir del estudio de la dinámica temporal de la respuesta inflamatoria a lo largo de la exposición a la dieta así como de la intervención in vitro, puede inferirse que la participación de la microglía y su interacción con las neuronas mediante vesículas extracelulares es fundamental para el desarrollo de la patología neurológica asociada a la disfunción metabólica.

The incidence of metabolic disorders including obesity, type 2 diabetes and metabolic syndrome has increased drastically in the last decades and represents an important problem to public health. At the same time, they constitute one of the main risk factors for the development of neurodegenerative disorders such as Alzheimer´s disease (AD), which has a growing impact in modern societies. Insulin resistance and inflammation promote cognitive impairment, playing a key role in the development of AD. However, little is known as regards the cellular and molecular pathways involved in the central nervous system. The aim of this Thesis was to study the impact of a moderate HFD in the limbic system during juvenile stages, where brain connectivity and physiology are subject to plain maturation, as well as the possible mechanisms involved. To this end, C57BL/6J male mice were exposed to a HFD or control diet since weaning and until 2 or 5 months of age. HFD induced insulin resistance together with peripheral and central inflammation, in absence of obesity. In the hippocampus, glial activation was observed in association to a decreased neurogenic capacity in the dentate gyrus and alterations in the structural plasticity of CA1 neurons, with a predominance of immature or thin dendritic spines. HFD mice showed a diminished capacity to build a nest, along with cognitive deficits and emotional alterations related to anxiety and depression. In order to study the role of glia-neuron interaction in the context of a metabolic insult in deep, we assessed the effect the saturated fatty acid palmitate (PA) in murine microglia primary cultures. PA-exposed microglia showed a pro-inflammatory phenotype and released extracellular vesicles to the conditioned media. Isolated microvesicles and exosomes were incubated with primary mouse neurons. In particular, exosomes derived from PA-exposed microglia induced alterations in dendritic spine morphology, with a predominance of immature thin spines, in consonance with the results obtained in the in vivo HFD model. This Thesis depicts several alterations in neurological parameters as a consequence of an early exposure to a moderately high fat diet, many of which are common to AD-like disorders. As a result of assessing the temporal dynamics of the inflammatory response throughout HFD exposure, together with the outcome of the in vitro approach, we can infer that the role of microglia and its interaction with neurons by means of extracellular vesicles is crucial for the development of brain damage associated to metabolic dysfunction.

Author affiliation: Vinuesa, María Ángeles. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.

Abstract:

There is a constant need to assess spatial memory in small rodents to elucidate the basics of cognition in neuroscience experiments. Thus, the significance of the Barnes maze in the biology of hippocampal and cortical neural function cannot be overemphasized. Despite the wide use of the Barnes maze, the effect of maze task training on the structure of hippocampal neurons is yet to be elucidated. Adult Sprague-Dawley rats were subjected to intense training on the Barnes maze (3 months). Subsequently, the hippocampus (cornus ammonis and dentate gyrus) of separate sets of rats was processed for Golgi Colonnier techniques (silver impregnation) and adenoviral-green fluorescent protein labeling (immunohistochemistry). Our results showed that training the animals on the Barne maze increased spinogenesis significantly in the cornus ammonis and dentate gyrus neurons. In addition, we identified a critical time point at which the rats habituated to the trial without escaping box (the probe trial) and could not be tested further in the maze. Taken together, we deduced that a prolonged test on the dry land maze facilitated habituation and caused an increase in hippocampal dendritic spine count. As such, the dry land maze is a suitable paradigm for assessing spatial memory in rats. However, precautions should be taken in selecting suitable experimental controls on the basis of the duration of a study.

Author affiliation: Uriarte Donati, Maia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; Argentina

Author affiliation: Ogundele, Olalekan Michael. State University of Louisiana; Estados Unidos

Author affiliation: Pardo, Joaquin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentina

Abstract:

The nervous system is populated by diverse types of neurons, each of which has dendritic trees with strikingly different morphologies. These neuron-specific morphologies determine how dendritic trees integrate thousands of synaptic inputs to generate different firing properties. To ensure proper neuronal function and connectivity, it is necessary that dendrite patterns are precisely controlled and coordinated with synaptic activity. Here, we summarize the molecular and cellular mechanisms that regulate the formation of cell type-specific dendrite patterns during development. We focus on different aspects of vertebrate dendrite patterning that are particularly important in determining the neuronal function; such as the shape, branching, orientation and size of the arbors as well as the development of dendritic spine protrusions that receive excitatory inputs and compartmentalize postsynaptic responses. Additionally, we briefly comment on the implications of aberrant dendritic morphology for nervous system disease.

Author affiliation: Ledda, Maria Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina

Author affiliation: Paratcha, Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina

Abstract:

Neddylation is a ubiquitylation-like pathway that controls cell cycle and proliferation by covalently conjugating Nedd8 to specific targets. However, its role in neurons, nonreplicating postmitotic cells, remains unexplored. Here we report that Nedd8 conjugation increased during postnatal brain development and is active in mature synapses, where many proteins are neddylated. We show that neddylation controls spine development during neuronal maturation and spine stability in mature neurons. We found that neddylated PSD-95 was present in spines and that neddylation on Lys202 of PSD-95 is required for the proactive role of the scaffolding protein in spine maturation and synaptic transmission. Finally, we developed Nae1 CamKIIα-CreERT2 mice, in which neddylation is conditionally ablated in adult excitatory forebrain neurons. These mice showed synaptic loss, impaired neurotransmission and severe cognitive deficits. In summary, our results establish neddylation as an active post-translational modification in the synapse regulating the maturation, stability and function of dendritic spines.

Author affiliation: Vogl, Annette M.. Instituto Max Planck de Psiquiatria de Munich; Alemania

Author affiliation: Brockmann, Marisa M.. Instituto Max Planck de Psiquiatria de Munich; Alemania

Author affiliation: Giusti, Sebastian Alejandro. Instituto Max Planck de Psiquiatria de Munich; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Author affiliation: MacCarrone, Giuseppina. Instituto Max Planck de Psiquiatria de Munich; Alemania

Author affiliation: Vercelli, Claudia Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina

Author affiliation: Bauder, Corinna A.. Instituto Max Planck de Psiquiatria de Munich; Alemania

Author affiliation: Richter, Julia S.. Instituto Max Planck de Psiquiatria de Munich; Alemania. Instituto Max Planck de Psiquiatria de Munich; Alemania

Author affiliation: Roselli, Francesco. Universita Degli Studi Di Bari; Italia

Author affiliation: Hafner, Anne-Sophie. Universite de Bordeaux; Francia

Author affiliation: Dedic, Nina. Instituto Max Planck de Psiquiatria de Munich; Alemania

Author affiliation: Wotjak, Carsten T.. Instituto Max Planck de Psiquiatria de Munich; Alemania

Author affiliation: Vogt Weisenhorn, Daniela M.. Institute Of Developmental Genetics; Alemania

Author affiliation: Choquet, Daniel. Universite de Bordeaux; Francia

Author affiliation: Turck, Christoph W.. Instituto Max Planck de Psiquiatria de Munich; Alemania

Author affiliation: Stein, Valentin. Universitaet Bonn; Alemania

Author affiliation: Deussing, Jan M.. Instituto Max Planck de Psiquiatria de Munich; Alemania

Author affiliation: Refojo, Damian. Instituto Max Planck de Psiquiatria de Munich; Alemania

Abstract:

The proper formation and morphogenesis of dendrites is essential to the establishment of neuronal connectivity. We report that 2 members of the Pea3 family of transcription factors, Etv4 and Etv5, are expressed in hippocampal neurons during the main period of dendritogenesis, suggesting that they have a function in dendrite development. Here, we show that these transcription factors are physiological regulators of growth and arborization of pyramidal cell dendrites in the developing hippocampus. Gain and loss of function assays indicate that Etv4 and Etv5 are required for proper development of hippocampal dendritic arbors and spines. We have found that in vivo deletion of either Etv4 or Etv5 in hippocampal neurons causes deficits in dendrite size and complexity, which are associated with impaired cognitive function. Additionally, our data support the idea that Etv4 and Etv5 are part of a brain-derived neurotrophic factor–mediated transcriptional program required for proper hippocampal dendrite connectivity and plasticity.

Author affiliation: Fontanet, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina

Author affiliation: Rios, Antonella Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina

Author affiliation: Alsina, Fernando Cruz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina

Author affiliation: Paratcha, Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina

Author affiliation: Ledda, Maria Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina

Abstract:

Cerebellar cortical throughput involved in motor control comprises granule cells (GCs) and Purkinje cells (PCs), both of which receive inhibitory GABAergic input from interneurons. The GABAergic input to PCs is essential for learning and consolidation of the vestibulo-ocular reflex, but the role of GC excitability remains unclear. We now disrupted the Kcc2 K-Cl cotransporter specifically in either cell type to manipulate their excitability and inhibition by GABA A-receptor Cl - channels. Although Kcc2 may have a morphogenic role in synapse development, Kcc2 disruption neither changed synapse density nor spine morphology. In both GCs and PCs, disruption of Kcc2, but not Kcc3, increased [Cl -] i roughly two-fold. The reduced Cl - gradient nearly abolished GABA-induced hyperpolarization in PCs, but in GCs it merely affected excitability by membrane depolarization. Ablation of Kcc2 from GCs impaired consolidation of long-term phase learning of the vestibulo-ocular reflex, whereas baseline performance, short-term gain-decrease learning and gain consolidation remained intact. These functions, however, were affected by disruption of Kcc2 in PCs. GC excitability plays a previously unknown, but specific role in consolidation of phase learning.

Author affiliation: Seja, Patricia. Leibniz-Institut für Molekulare Pharmakologie; Alemania. Max-Delbruck-Centrum für Molekulare Medizin; Alemania

Author affiliation: Schonewille, Martijn. Erasmus MC; Países Bajos

Author affiliation: Spitzmaul, Guillermo Federico. Leibniz-Institut für Molekulare Pharmakologie; Alemania. Max-Delbruck-Centrum für Molekulare Medizin; Alemania

Author affiliation: Badura, Aleksandra. Erasmus MC; Países Bajos

Author affiliation: Klein, Ilse. Universitat Hamburg; Alemania

Author affiliation: Rudhard, York. Universitat Hamburg; Alemania

Author affiliation: Wisden, William. Imperial College London; Reino Unido

Author affiliation: Hübner, Christian A. Universitat Hamburg; Alemania. Universitat Jena; Alemania

Author affiliation: De Zeeuw, Chris I. Erasmus MC; Países Bajos. Charite-Universitatsmedizin Berlin; Alemania

Author affiliation: Jentsch, Thomas J. Leibniz-Institut für Molekulare Pharmakologie; Alemania. Universitat Hamburg; Alemania. Charite-Universitatsmedizin Berlin; Alemania