European Brain Research Institute

Rome, Italy

European Brain Research Institute

Rome, Italy
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Mendez P.,University of Geneva | Mendez P.,European Brain Research Institute | Garcia-Segura L.M.,Instituto Cajal | Muller D.,University of Geneva
Hippocampus | Year: 2011

Estrogens regulate dendritic spine density, but the mechanism and significance of this effect for brain networks remain unknown. We used repetitive imaging over several days to investigate how 17β-estradiol affected the turnover and long-term behavior of dendritic spines in CA1 cells of hippocampal slice cultures. We find that 17β-estradiol and serum in the culture medium tightly regulated spine density by promoting an increase in the rate of new spine formation and their transformation into synapses, without affecting spine elimination or stability. New spines formed during a transient 17β-estradiol application were preferentially eliminated upon removal of the hormone, in contrast with pre-existing spines that remained unaffected. Our results reveal that 17β-estradiol transiently regulates the complexity of hippocampal circuits without causing major alterations of pre-existing networks. © 2010 Wiley Periodicals, Inc.


Mendez P.,European Brain Research Institute | Mendez P.,University of Geneva | Pazienti A.,European Brain Research Institute | Szabo G.,H+ Technology | Bacci A.,European Brain Research Institute
Journal of Neuroscience | Year: 2012

Correct brain functioning relies on the precise activity of a myriad of synapses assembling neurons in complex networks. In the hippocampus, highly diverse inhibitory circuits differently govern several physiologically relevant network activities. Particularly, perisomatic inhibition provided by specific interneurons was proposed to control emotional states, and could therefore be affected by mood disorders and their therapy. We found that both chronic and acute administration of two major antidepressants, imipramine and fluoxetine, strongly and directly altered GABA-mediated (GABAergic) hippocampal neurotransmission in mice and rats, independently of their effects on amine reuptake systems. These drugs affected GABA release from synapses formed by fast-spiking cells, but not interneurons expressing cannabinoid receptor type 1, resulting in the disruption of γ oscillations. This differential effect, shared by two types of antidepressants, suggests a new mechanism of action of these medications, and a possible role of perisomatic inhibition in depressive disorders. © 2012 the authors.


Cavallucci V.,IRCCS Fondazione Santa Lucia | Ferraina C.,European Brain Research Institute | D'Amelio M.,IRCCS Fondazione Santa Lucia | D'Amelio M.,Biomedical University of Rome
Current Pharmaceutical Design | Year: 2013

Neuronal transmission and functional synapses require mitochondria, which are mainly involved in the generation of energy (ATP and NAD+), regulation of cell signaling and calcium homeostasis. Particularly intriguing is emerging data suggesting the relationship between mitochondria and neurotrophic factors that can act at the synaptic level promoting neuronal transmission and plasticity. On the other hand, disturbances in mitochondrial functions might contribute to impaired synaptic transmission and neuronal degeneration in Alzheimer's Disease and other chronic and acute neurodegenerative disorders. Here, we review the molecular mediators controling mitochondrial function and their impact on synaptic dysfunction associated with the pathogenesis of Alzheimer's Disease. © 2013 Bentham Science Publishers.


Calissano P.,CNR Institute of Neurobiology and Molecular Medicine | Calissano P.,European Brain Research Institute | Matrone C.,CNR Institute of Neurobiology and Molecular Medicine | Amadoro G.,CNR Institute of Neurobiology and Molecular Medicine
Developmental Neurobiology | Year: 2010

Converging lines of evidence on the possible connection between NGF signaling and Alzheimer's diseases (AD) are unraveling new facets which could depict this neurotrophin (NTF) in a more central role. AD animal models have provided evidence that a shortage of NGF supply may induce an AD-like syndrome. In vitro experiments, moreover, are delineating a possible temporal and causal link between APP amiloydogenic processing and altered post-translational tau modifications. After NGF signaling interruption, the pivotal upstream players of the amyloid cascade (APP, β-secretase, and active form of γ-secretase) are up-regulated, leading to an increased production of amyloid β peptide (Aβ) and to its intracellular aggregation in molecular species of different sizes. Contextually, the Aβ released pool generates an autocrine toxic loop in the same healthy neurons. At the same time tau protein undergoes anomalous, GSKβ-mediated, phosphorylation at specific pathogenetic sites (Ser262 and Thr 231), caspase(s) and calpain- I- mediated truncation, detachment from microtubules with consequent cytoskeleton collapse and axonal transport impairment. All these events are inhibited when the amyloidogenic processing is reduced by β and γ secretase inhibitors or anti-Aβ antibodies and appear to be causally correlated to TrkA, p75CTF, Aβ, and PS1 molecular association in an Aβ-mediated fashion. In this scenario, the so-called trophic action exerted by NGF (and possibly also by other neurotrophins) in these targets neurons is actually the result of an anti-amyloidogenic activity. © 2010 Wiley Periodicals, Inc.


Zacchi P.,International School for Advanced Studies | Antonelli R.,International School for Advanced Studies | Cherubini E.,International School for Advanced Studies | Cherubini E.,European Brain Research Institute
Frontiers in Cellular Neuroscience | Year: 2014

Gephyrin is a multifunctional scaffold protein essential for accumulation of inhibitory glycine and GABAA receptors at post-synaptic sites. The molecular events involved in gephyrin-dependent GABAA receptor clustering are still unclear. Evidence has been recently provided that gephyrin phosphorylation plays a key role in these processes. Gephyrin post-translational modifications have been shown to influence the structural remodeling of GABAergic synapses and synaptic plasticity by acting on post-synaptic scaffolding properties as well as stability. In addition, gephyrin phosphorylation and the subsequent phosphorylation-dependent recruitment of the chaperone molecule Pin1 provide a mechanism for the regulation of GABAergic signaling. Extensively characterized as pivotal enzyme controlling cell proliferation and differentiation, the prolyl-isomerase activity of Pin1 has been shown to regulate protein synthesis necessary to sustain the late phase of long-term potentiation at excitatory synapses, which suggests its involvement at synaptic sites. In this review we summarize the current state of knowledge of the signaling pathways responsible for gephyrin post-translational modifications. We will also outline future lines of research that might contribute to a better understanding of molecular mechanisms by which gephyrin regulates synaptic plasticity at GABAergic synapses. © 2014 Zacchi, Antonelli and Cherubini.


Marchetti M.,European Brain Research Institute | Marie H.,European Brain Research Institute | Marie H.,French National Center for Scientific Research
Reviews in the Neurosciences | Year: 2011

Transgenic (Tg) mouse models of Alzheimer's disease (AD) are used to investigate mechanisms underlying disease pathology and identify therapeutic strategies. Most Tg AD models, which at least partly recapitulate the AD phenotype, are based on insertion of one or more human mutations (identified in Familial AD) into the mouse genome, with the notable exception of the anti-NGF mouse, which is based on the cholinergic unbalance hypothesis. It has recently emerged that impaired hippocampal synaptic function is an early detectable pathological alteration, well before the advanced stage of amyloid plaque accumulation and general cell death. Nevertheless, electrophysiological studies performed on different Tg models or on the same model by different research groups have yielded contrasting results. We therefore summarized data from original research papers studying hippocampal synaptic function using electrophysiology, to review what we have learned so far. We analyzed results obtained using the following Tg models: (1) single/multiple APP mutations; (2) single presenilin (PS) mutations; (3) APPxPS1 mutations; (4) APPxPS1xtau mutations (3xTg); and (5) anti-NGF expressing (AD11) mice. We observed that the majority of papers focus on excitatory basic transmission and long-term potentiation, while few studies evaluate inhibitory transmission and long-term depression. We searched for common synaptic alterations in the various models that might underlie the memory deficits observed in these mice. We also considered experimental variables that could explain differences in the reported results and briefly discuss successful rescue strategies. These analyses should prove useful for future design of electrophysiology experiments to assess hippocampal function in AD mouse models. © 2011 by Walter de Gruyter Berlin Boston.


Deleuze C.,Groupe Hospitalier Pitie Salpetriere | Pazienti A.,European Brain Research Institute | Bacci A.,Groupe Hospitalier Pitie Salpetriere | Bacci A.,University Pierre and Marie Curie
Current Opinion in Neurobiology | Year: 2014

Fast synaptic inhibition sculpts all forms of cortical activity by means of a specialized connectivity pattern between highly heterogeneous inhibitory interneurons and principal excitatory cells. Importantly, inhibitory neurons connect also to each other extensively, following a detailed blueprint, and, indeed, specific forms of disinhibition affect important behavioral functions. Here we discuss a peculiar form of cortical disinhibition: the massive autaptic self-inhibition of parvalbumin-(PV) positive basket cells. Despite being described long ago, autaptic inhibition onto PV basket cells is rarely included in cortical circuit diagrams, perhaps because of its still elusive function. We propose here a potential dual role of autaptic feedback inhibition in temporally coordinating PV basket cells during cortical network activity. © 2013 Elsevier Ltd.


Gatliff J.,Royal Veterinary College University of London | Campanella M.,Royal Veterinary College University of London | Campanella M.,University College London | Campanella M.,European Brain Research Institute
Current Molecular Medicine | Year: 2012

In mammals, mitochondria are central in maintaining normal cell function and dissecting the pathways that govern their physiology and pathology is therefore of utmost importance. For a long time, the science world has acknowledged the Translocator Protein (TSPO), an intriguing molecule that, through its position and association with biological processes, stands as one of the hidden regulatory pathways in mitochondrial homeostasis. Here we aim to review the literature and highlight what links TSPO to mitochondrial homeostasis in order to delineate its contribution in the functioning and malfunctioning of this critical organelle. In detail, we will discuss: 1) TSPO localization and interplay with controlling phenomena of mitochondria (e.g. mPTP); 2) TSPO interaction with the prominent mitochondrial player VDAC; consider evidence on how TSPO relates to 3) mitochondrial energy production; 4) Ca2+ signalling and 5) the generation of Reactive Oxygen Species (ROS) before finally describing 6) its part in apoptotic cell death. In essence, we hope to demonstrate the intimate involvement TSPO has in the regulation of mitochondrial homeostasis and muster attention towards this molecule, which is equally central for both cellular and mitochondrial biology. © 2012 Bentham Science Publishers.


Faccenda D.,Royal Veterinary College University of London | Campanella M.,Royal Veterinary College University of London | Campanella M.,European Brain Research Institute
International Journal of Cell Biology | Year: 2012

In mammals, the mitochondrial F1Fo-ATPsynthase sets out the energy homeostasis by producing the bulk of cellular ATP. As for every enzyme, the laws of thermodynamics command it; however, it is privileged to have a dedicated molecular regulator that controls its rotation. This is the so-called ATPase Inhibitory Factor 1 (IF1) that blocks its reversal to avoid the consumption of cellular ATP when the enzyme acts as an ATP hydrolase. Recent evidence has also demonstrated that IF1 may control the alignment of the enzyme along the mitochondrial inner membrane, thus increasing the interest for the molecule. We conceived this review to outline the fundamental knowledge of the F1Fo-ATPsynthase and link it to the molecular mechanisms by which IF1 regulates its way of function, with the ultimate goal to highlight this as an important and possibly unique means to control this indispensable enzyme in both physiological and pathological settings. Copyright © 2012 Danilo Faccenda and Michelangelo Campanella.


In the neocortex, the coexistence of temporally locked excitation and inhibition governs complex network activity underlying cognitive functions, and is believed to be altered in several brain diseases. Here we show that this equilibrium can be unlocked by increased activity of layer 5 pyramidal neurons of the mouse neocortex. Somatic depolarization or short bursts of action potentials of layer 5 pyramidal neurons induced a selective long-term potentiation of GABAergic synapses (LTPi) without affecting glutamatergic inputs. Remarkably, LTPi was selective for perisomatic inhibition from parvalbumin basket cells, leaving dendritic inhibition intact. It relied on retrograde signaling of nitric oxide, which persistently altered presynaptic GABA release and diffused to inhibitory synapses impinging on adjacent pyramidal neurons. LTPi reduced the time window of synaptic summation and increased the temporal precision of spike generation. Thus, increases in single cortical pyramidal neuron activity can induce an interneuron-selective GABAergic plasticity effectively altering the computation of temporally coded information.

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