Achucarro Basque Center for Neuroscience

Basque, Spain

Achucarro Basque Center for Neuroscience

Basque, Spain
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News Article | May 19, 2017
Site: www.sciencedaily.com

The annual mortality rate in childhood cancer of the sympathetic nervous system, or neuroblastoma, is 10 per million between the ages of 0 and 4. The collaborative work between Basque and Valencian researchers has served to identify some genetic mutations that will help to improve the treatment of this disease. Researchers at the Instituto de Investigación Sanitaria La Fe (Institute of Healthcare Research La Fe) in Valencia led by Jaime Font de Mora, in collaboration with José Luis Zugaza, an Ikerbasque researcher at the UPV/EHU-University of the Basque Country and the "Achucarro Basque Center for Neuroscience," have by means of NGS (Next Generation Sequencing) identified mutations in the Tiam1 gene that predict a better prognosis for neuroblastoma patients. A neuroblastoma is a solid, extracranial tumor more frequent in childhood. It accounts for 7% of all paediatric cancers and is the cause of 15% of the total number of deaths resulting from oncological processes in childhood. The incidence of it ranges between 8 and 10 cases per million children. Family cases of neuroblastoma have been described but they are extremely rare. Right now, it is not known how this rare type of cancer originates. The study reveals that these mutations that anticipate the progression of this disease are located in various Tiam1 domains related to the Ras and Rac GTPases and also with Myc; all these proteins are involved in the aetiology and progression of this type of cancer. The results have been published in the journal Oncotarget, which specialises in works dealing with targets for different types of cancers. These results suggest that the signalosome controlled by Tiam1 may be essential in the development of the neuroblastoma and, therefore, Tiam1 is positioned as a target that could help to improve the effectiveness of neuroblastoma treatment. The next step is to incorporate these studies into clinical practice to improve the tools and procedures in the diagnosis with a view to implementing earlier treatments for the children affected.


Tonnesen J.,Achucarro Basque Center for Neuroscience | Tonnesen J.,University of the Basque Country | Kokaia M.,Lund University
Clinical Science | Year: 2017

Over the past decade, 'optogenetics' has been consolidated as a game-changing tool in the neuroscience field, by allowing optical control of neuronal activity with high cell-type specificity. The ability to activate or inhibit targeted neurons at millisecond resolution not only offers an investigative tool, but potentially also provides a therapeutic intervention strategy for acute correction of aberrant neuronal activity. As efficient therapeutic tools are in short supply for neurological disorders, optogenetic technology has therefore spurred considerable enthusiasm and fostered a new wave of translational studies in neuroscience. Epilepsy is among the disorders that have been widely explored. Partial epilepsies are characterized by seizures arising from excessive excitatory neuronal activity that emerges from a focal area. Based on the constricted seizure focus, it appears feasible to intercept partial seizures by acutely shutting down excitatory neurons by means of optogenetics. The availability of both inhibitory and excitatory optogenetic probes, along with the available targeting strategies for respective excitatory or inhibitory neurons, allows multiple conceivable scenarios for controlling abnormal circuit activity. Several such scenarios have been explored in the settings of experimental epilepsy and have provided encouraging translational findings and revealed interesting and unexpected new aspects of epileptogenesis. However, it has also emerged that considerable challenges persist before clinical translation becomes feasible. This review provides a general introduction to optogenetics, and an overview of findings that are relevant for understanding how optogenetics may be utilized therapeutically as a highly innovative treatment for epilepsy. © 2017 The Author(s).


Sierra A.,Achucarro Basque Center for Neuroscience | Sierra A.,University of the Basque Country | Sierra A.,Ikerbasque | Abiega O.,Achucarro Basque Center for Neuroscience | And 3 more authors.
Frontiers in Cellular Neuroscience | Year: 2013

Microglia are the resident brain macrophages and they have been traditionally studied as orchestrators of the brain inflammatory response during infections and disease. In addition, microglia has a more benign, less explored role as the brain professional phagocytes. Phagocytosis is a term coined from the Greek to describe the receptor-mediated engulfment and degradation of dead cells and microbes. In addition, microglia phagocytoses brain-specific cargo, such as axonal and myelin debris in spinal cord injury or multiple sclerosis, amyloid-? deposits in Alzheimer's disease, and supernumerary synapses in postnatal development. Common mechanisms of recognition, engulfment and degradation of the different types of cargo are assumed, but very little is known about the shared and specific molecules involved in the phagocytosis of each target by microglia. More importantly, the functional consequences of microglial phagocytosis remain largely unexplored. Overall, phagocytosis is considered a beneficial phenomenon, since it eliminates dead cells and induces an anti-inflammatory response. However, phagocytosis can also activate the respiratory burst, which produces toxic reactive oxygen species. Phagocytosis has been traditionally studied in pathological conditions, leading to the assumption that microglia have to be activated in order to become efficient phagocytes. Recent data, however, has shown that unchallenged microglia phagocytose apoptotic cells during development and in adult neurogenic niches, suggesting an overlooked role in brain remodeling throughout the normal lifespan. The present review will summarize the current state of the literature regarding the role of microglial phagocytosis in maintaining tissue homeostasis in health as in disease. © © 2013 Sierra, Abiega, Shahraz and Neumann.


Domercq M.,University of the Basque Country | Domercq M.,Achucarro Basque Center for Neuroscience | Mato S.,University of the Basque Country | Mato S.,Achucarro Basque Center for Neuroscience | And 8 more authors.
GLIA | Year: 2013

Much of the cell death following episodes of anoxia and ischemia in the mammalian central nervous system has been attributed to extracellular accumulation of glutamate and ATP, which causes a rise in [Ca2+]i, loss of mitochondrial potential, and cell death. However, restoration of blood flow and reoxygenation are frequently associated with exacerbation of tissue injury (the oxygen paradox). Herein we describe a novel signaling pathway that is activated during ischemia-like conditions (oxygen and glucose deprivation; OGD) and contributes to ischemia-induced oligodendroglial cell death. OGD induced a retarded and sustained increase in extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation after restoring glucose and O2 (reperfusion-like conditions). Blocking the ERK1/2 pathway with the MEK inhibitor UO126 largely protected oligodendrocytes against ischemic insults. ERK1/2 activation was blocked by the high-affinity Zn2+ chelator TPEN, but not by antagonists of AMPA/kainate or P2X7 receptors that were previously shown to be involved in ischemic oligodendroglial cell death. Using a high-affinity Zn2+ probe, we showed that ischemia induced an intracellular Zn2+ rise in oligodendrocytes, and that incubation with TPEN prevented mitochondrial depolarization and ROS generation after ischemia. Accordingly, exposure to TPEN and the antioxidant Trolox reduced ischemia-induced oligodendrocyte death. Moreover, UO126 blocked the ischemia-induced increase in poly-[ADP]-ribosylation of proteins, and the poly[ADP]-ribose polymerase 1 (PARP-1) inhibitor DPQ significantly inhibited ischemia-induced oligodendroglial cell death-demonstrating that PARP-1 was required downstream in the Zn2+-ERK oligodendrocyte cell death pathway. Chelation of cytosolic Zn2+, blocking ERK signaling, and antioxidants may be beneficial for treating CNS white matter ischemia-reperfusion injury. Importantly, all the inhibitors of this pathway protected oligodendrocytes when applied after the ischemic insult. © 2012 Wiley Periodicals, Inc.


Vazquez-Villoldo N.,University of the Basque Country | Vazquez-Villoldo N.,Achucarro Basque Center for Neuroscience | Vazquez-Villoldo N.,CIBER ISCIII | Domercq M.,University of the Basque Country | And 8 more authors.
GLIA | Year: 2014

Microglia, the resident immune cells of the central nervous system, responds to brain disarrangements by becoming activated to contend with brain damage. Here we show that the expression of P2X4 receptors is upregulated in inflammatory foci and in activated microglia in the spinal cord of rats with experimental autoimmune encephalomyelitis (EAE) as well as in the optic nerve of multiple sclerosis patients. To study the role of P2X4 receptors in microgliosis, we activated microglia with LPS in vitro and in vivo. We observed that P2X4 receptor activity in vitro was increased in LPS-activated microglia as assessed by patch-clamp recordings. In addition, P2X4 receptor blockade significantly reduced microglial membrane ruffling, TNFα secretion and morphological changes, as well as LPS-induced microglial cell death. Accordingly, neuroinflammation provoked by LPS injection in vivo induced a rapid microglial loss in the spinal cord that was totally prevented or potentiated by P2X4 receptor blockade or facilitation, respectively. Within the brain, microglia in the hippocampal dentate gyrus showed particular vulnerability to LPS-induced neuroinflammation. Thus, microglia processes in this region retracted as early as 2 h after injection of LPS and died around 24 h later, two features which were prevented by blocking P2X4 receptors. Together, these data suggest that P2X4 receptors contribute to controlling the fate of activated microglia and its survival. © 2013 Wiley Periodicals, Inc.


Sierra A.,Achucarro Basque Center for Neuroscience | Sierra A.,Ikerbasque | Sierra A.,University of the Basque Country | de Castro F.,Instituto Cajal | And 4 more authors.
GLIA | Year: 2016

The word “glia” was coined in the mid-19th century and defined as “the nerve glue”. For decades, it was assumed to be a uniform matrix, until cell theorists raised the “neuron doctrine” which stipulated that nervous tissue was composed of individual cells. The term “astrocytes” was introduced in the late 19th century as a synonym for glial cells, but it was Santiago Ramón y Cajal who defined a “third element” distinct from glial cells (astrocytes) and neurons. It was not until 1919 when Pío del Río-Hortega, an alumnus of the Cajal School, introduced the modern terms we use today, and thoroughly described both “oligodendrocytes” and “microglia” to clearly distinguish them from astrocytes. In a series of four papers published that year in Spanish, Río-Hortega described the distribution and morphological phenotype of microglia. He also noted that these cells were the origin of the rod cells described earlier in pathologic tissue, and recognized that resting microglia transformed into an ameboid phenotype in different types of brain diseases and pathologies. He also noted the mesodermal origin of these cells and recognized their phagocytic capacity. We here provide the first English translation of these landmark series of papers, which paved the way for modern glial research. To heighten the value and accessibility of these classic papers and their original figures, an introduction to this critical period of neuroscience is provided, along with unpublished photographs. By adding comments to the translated text, we provide sufficient context so that contemporary scientists may fully appreciate it. GLIA 2016;64:1801–1840. © 2016 Wiley Periodicals, Inc.


Encinas J.M.,Achucarro Basque Center for Neuroscience | Encinas J.M.,Ikerbasque | Encinas J.M.,University of the Basque Country | Fitzsimons C.P.,University of Amsterdam
Advanced Drug Delivery Reviews | Year: 2017

Adult neural stem and progenitor cells (NSPCs) offer a unique opportunity for neural regeneration and niche modification in physiopathological conditions, harnessing the capability to modify from neuronal circuits to glial scar. Findings exposing the vast plasticity and potential of NSPCs have accumulated over the past years and we currently know that adult NSPCs can naturally give rise not only to neurons but also to astrocytes and reactive astrocytes, and eventually to oligodendrocytes through genetic manipulation. We can consider NSPCs as endogenous flexible tools to fight against neurodegenerative and neurological disorders and aging. In addition, NSPCs can be considered as active agents contributing to chronic brain alterations and as relevant cell populations to be preserved, so that their main function, neurogenesis, is not lost in damage or disease. Altogether we believe that learning to manipulate NSPC is essential to prevent, ameliorate or restore some of the cognitive deficits associated with brain disease and injury, and therefore should be considered as target for future therapeutic strategies. The first step to accomplish this goal is to target them specifically, by unveiling and understanding their unique markers and signaling pathways. © 2017.


News Article | November 10, 2016
Site: www.eurekalert.org

It has been known for some time that the extracts of the Cannabis plant, just like synthetic cannabinoids and those produced by the brain itself, join up with type 1 (CB1) cannabinoid receptors located in the nerve endings of the neurons, and inhibit the release of chemical messengers (neurotransmitters) in the communication areas between the nerve cells. The knowledge about the way cannabinoids work has been expanded in recent years when it was shown that the CB1 receptor is also located in and functions in the mitochondria of the neurons; mitochondria are the organelles responsible for producing cell energy. A new piece of research, which has been published in the online version of the journal Nature, has now gone a step further on discovering that the amnesia caused by cannabinoids needs the activation of the CB1 cannabinoid receptors located in the mitochondria of the hippocampus, the brain structure involved in memory formation. To obtain the results of this research, led by Dr Giovanni Marsicano of the University of Bordeaux, the contribution of the following doctors was crucial: Nagore Puente, Leire Reguero, Izaskun Elezgarai and Pedro Grandes; they are neuroscientists in the Department of Neurosciences of the UPV/EHU's Faculty of Medicine and Nursing and of the Achucarro Basque Center for Neuroscience and they also participated in a previous discovery about the location and functioning of the CB1 receptor in the mitochondria. In this new piece of research, the researchers used a broad range of cutting-edge experimental techniques and saw that the genetic elimination of the CB1 receptor from the mitochondria of the hippocampus prevents memory loss, the reduction in mitochondrial movement and the decrease in neural communication induced by the cannabinoids. This research also revealed that the amnesia caused by cannabinoids and the related cell processes are linked to an acute alteration in bioenergetic mitochondrial activity owing to the direct activation of the CB1 receptors in the mitrochondria. This activation leads to the inhibiting of the cannabinoid signalling cascade inside the mitochondria and cell respiration diminishes as a result. This reduction in cell respiration through cannabinoids is not restricted to the brain as a similar phenomenon occurs in skeletal and cardiac muscle, as has recently been published in another piece of research by the group of Dr Grandes. "Mitochondrial malfunctioning could have serious consequences for the brain. For example, chronic mitochondrial dysfunction is involved in the pathogenesis of neurodegenerative diseases, strokes or disorders associated with ageing. However, the involvement of the acute variation in mitochondrial activity in higher brain functions, such as memory, was unknown," pointed out Dr Grandes. So this research has revealed that the CB1 cannabinoid receptors in the mitochondria regulate the memory processes by modulating mitochondrial energy metabolism. Furthermore, although cannabinoid by-products have a well-known therapeutic potential, their use is limited by the significant adverse effects that emerge when acting on CB1 receptors, including memory loss. The results of this research suggest that "a selective intervention on specific CB1 cannabinoid receptors located in the brain in certain specific neurone compartments could be of interest with a view to developing new therapeutic tools based on the most effective and safest cannabinoids in the treatment of certain brain diseases," explained Dr Grandes. "This research is the result of 6 years' work in which 28 researchers have participated. In our case it would not have been possible without the funding received from the UPV/EHU, the Basque Government and Spanish institutions, which have placed their trust in us even during these years of tremendous cutbacks for research; this is something I recognise and which I am grateful for," concluded Pedro Grandes. Pedro Grandes has recently been Visiting Professor at the University of Victoria, British Columbia, Canada, where he has been doing research work and teaching students of medicine and post-graduate students.


Pascual-Brazo J.,Catholic University of Leuven | Baekelandt V.,Catholic University of Leuven | Encinas J.M.,Achucarro Basque Center for Neuroscience | Encinas J.M.,Ikerbasque | Encinas J.M.,University of the Basque Country
Current Pharmaceutical Design | Year: 2014

Thirteen years have passed since the neurogenic hypothesis of depression was postulated. One of its aspects, that decreased neurogenesis could be causative of the onset of depression has been difficult to prove. Another aspect, the prediction that increasing neurogenesis would not only be supportive but also required to produce clinical results by antidepressants has gathered experimental validation. Thus a question arises: should new antidepressant strategies based solely on increasing neurogenesis be pursued? At the risk of disappointing the audience, we will not provide a straight answer to this question in this review, but we do hope to enlighten the reader regarding what is known about adult hippocampal neurogenesis, the indications and evidence of its involvement in the onset and treatment of depression, and the advances that have been made in the field in recent years. As we will recount here, the main body of support in favor of the neurogenic hypothesis of depression is based more on intimation than actual proof. However the rare examples that provide support are sufficiently robust to justify investment of resources and effort to clarify the issue, even if the involvement of neurogenesis, both in the etiology and the treatment of depression, is only partial and comprises only subtle components of this complex mental disorder. © 2014 Bentham Science Publishers.


News Article | November 10, 2016
Site: www.chromatographytechniques.com

It has been known for some time that the extracts of the Cannabis plant, just like synthetic cannabinoids and those produced by the brain itself, join up with type 1 (CB1) cannabinoid receptors located in the nerve endings of the neurons, and inhibit the release of chemical messengers (neurotransmitters) in the communication areas between the nerve cells. The knowledge about the way cannabinoids work has been expanded in recent years when it was shown that the CB1 receptor is also located in and functions in the mitochondria of the neurons. A new piece of research, which has been published in the online version of the journal Nature, has now gone a step further on discovering that the amnesia caused by cannabinoids needs the activation of the CB1 cannabinoid receptors located in the mitochondria of the hippocampus, the brain structure involved in memory formation. To obtain the results of this research, led by Giovanni Marsicano of the University of Bordeaux, the contribution of the following doctors was crucial--Nagore Puente, Leire Reguero, Izaskun Elezgarai and Pedro Grandes -- neuroscientists in the Department of Neurosciences of the UPV/EHU's Faculty of Medicine and Nursing and of the Achucarro Basque Center for Neuroscience. They also participated in a previous discovery about the location and functioning of the CB1 receptor in the mitochondria. In this new piece of research, the researchers used a broad range of cutting-edge experimental techniques and saw that the genetic elimination of the CB1 receptor from the mitochondria of the hippocampus prevents memory loss, the reduction in mitochondrial movement and the decrease in neural communication induced by the cannabinoids. This research also revealed that the amnesia caused by cannabinoids and the related cell processes are linked to an acute alteration in bioenergetic mitochondrial activity owing to the direct activation of the CB1 receptors in the mitrochondria. This activation leads to the inhibiting of the cannabinoid signaling cascade inside the mitochondria and cell respiration diminishes as a result. This reduction in cell respiration through cannabinoids is not restricted to the brain as a similar phenomenon occurs in skeletal and cardiac muscle, as has recently been published in another piece of research by the group of Grandes. "Mitochondrial malfunctioning could have serious consequences for the brain. For example, chronic mitochondrial dysfunction is involved in the pathogenesis of neurodegenerative diseases, strokes or disorders associated with ageing. However, the involvement of the acute variation in mitochondrial activity in higher brain functions, such as memory, was unknown," explained Grandes. So this research has revealed that the CB1 cannabinoid receptors in the mitochondria regulate the memory processes by modulating mitochondrial energy metabolism. Furthermore, although cannabinoid by-products have a well-known therapeutic potential, their use is limited by the significant adverse effects that emerge when acting on CB1 receptors, including memory loss. The results of this research suggest that "a selective intervention on specific CB1 cannabinoid receptors located in the brain in certain specific neurone compartments could be of interest with a view to developing new therapeutic tools based on the most effective and safest cannabinoids in the treatment of certain brain diseases," said Grandes. "This research is the result of six years' work, in which 28 researchers have participated. In our case it would not have been possible without the funding received from the UPV/EHU, the Basque Government and Spanish institutions, which have placed their trust in us even during these years of tremendous cutbacks for research; this is something I recognize and which I am grateful for," concluded Grandes.

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