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INSTITUTO CAJAL CSIC Sponsored by

With the collaboration of Fisher Scientific, Panlab Harvard and individual laboratories of the Instituto Cajal

Table of Contents Sponsors and collaborators .........................................................................

The 2013 CajalXmas ........................................................................................

Scientific program ............................................................................................

Speakers’ short CV ............................................................................................

Pedro Beltrán ................................................................................................

Pablo Méndez ................................................................................................

Shira Knafo .................................................................................................... Álvaro Llorente‐Berzal .............................................................................

Gertrudis Perea ............................................................................................

Miguel Valencia .............................................................................................

Bryan Strange ................................................................................................

Cristina Nombela .........................................................................................

Sponsors

Collaborators

Organized by Instituto Cajal

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The 2013 CajalXmas

A Christmas meeting at the Cajal The CajalXmas is a scientific and social meeting to bring together young and independent researchers from all over Spain and abroad to discuss and present their work in an informal environment during our traditional Christmas toast.

This one‐day meeting is conceived to attract neuroscientists with potential interest in joining our institute or independent researchers with interest in scientific collaboration and discussion Our focus This year we bring the focus to some of the Instituto Cajal strategic lines, including  Computational neuroscience  Traslational neuroscience  Neuroimaging studies

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Scientific Program

9.15‐9.30 Welcome and presentation

9.30‐10.00

Pedro Beltrán, Institut d’Investigació Biomèdica de Girona Arginine methylation: a novel post‐translational modification of voltage‐gated sodium channels

10.00‐10.30

Pablo Mendez, University of Geneva, Switzerland Cell autonomous regulation of inhibitory and excitatory synaptic inputs by neuronal activity

10.30‐11.00

Shira Knafo, Biophysics Unit, UPV/EHU‐CSIC, Bilbao Molecular blockade of synaptic depression prevents A‐induced cognitive decay

11.00‐11.30

Álvaro Llorente‐Berzal, Universidad Complutense de Madrid

Long‐lasting effects of THC and/or MDMA in an animal model of adolescent drug consumption.

11.30‐12.15

Coffee break

12.15‐12.45

Gertrudis Perea, Instituto Cajal, Madrid Astrocyte activation modulates response selectivity of visual cortex neurons in vivo

12.45‐13.15

Miguel Valencia, CIMA, Navarra Organizing information in the brain by means of cross‐frequency coupling mechanisms: Clinical and experimental scenarios

13.15‐13.45

Bryan Strange, Laboratory of Clinical Neuroscience, Centre for Biomedical Technology, UPM, Madrid How salience modulates episodic memory in humans

13.45‐14.15

Cristina Nombela, University of Cambridge, UK Genetic variation of cognitive deficits and brain function in newly diagnosed Parkinson’s disease

14.15‐14.30

Concluding remarks

14.30‐16.30

Vino de Navidad

16.30‐18.00

Visits to laboratories and informal discussion

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Pedro Beltrán Institut d’Investigació Biomèdica de Girona

Arginine methylation: a novel post‐translational modification of voltage‐gated sodium channels My research focuses on uncovering the molecular basis of cardiac and brain disorders. In particular, I am interested in regulation of ion channels by post‐translational modifications. I have recently identified arginine methylation as a novel post‐translational modification of the cardiac voltage‐gated sodium channel, NaV1.5. During the last months, I have observed that arginine methylation is conserved in brain isoforms of the sodium channel (NaV1.1 and NaV1.2). Current work aims at revealing the mechanisms that regulate NaV arginine methylation, including cross‐talk with other post‐translational modifications.

Publications Beltran‐Alvarez P, Espejo A, Schmauder R, Beltran C, Mrowka R, Linke T, Battle M, Perez‐Villa F, Perez GJ, Scornik FS, Benndorf K, Pagans S, Zimmer T, Brugada R. Protein Arginine Methyl Transferases ‐3 and ‐5 Regulate Electrophysiology and Cell Surface Expression of the Cardiac Sodium Channel. FEBS Lett. 2013, 587(19):3159‐65.

Riuró H, Beltran‐Alvarez P, Tarradas A, Selga E, Campuzano O, Verges M, Pagans S, Iglesias A, Brugada J, Brugada P, Vazquez FM, Perez GJ, ScornikFS, Brugada R. A missense mutation in the sodium channel β2 subunit reveals SCN2B as a new candidate gene for Brugada Syndrome.

Hum Mutat. 2013, 34(7):961‐6.

Kühner S, van Noort V, Betts MJ, Leo‐Macias A, Batisse C, Rode M, Yamada T, Maier T, Bader S, Beltran‐Alvarez P, Castaño‐Diez D, Chen WH, Devos D, Güell M, Norambuena T, Racke I, Rybin V, Schmidt A, Yus E, Aebersold R, Herrmann R, Böttcher B, Frangakis AS, Russell RB, Serrano L, Bork P, Gavin AC. Proteome organization in a genome‐reduced bacterium.

Science. 2009, 326(5957):1235‐40

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Pablo Méndez University of Geneva, Switzerland

Cell autonomous regulation of inhibitory and excitatory synaptic inputs by neuronal activity Synaptic activity is a major driving force for structural plasticity of both inhibitory and excitatory synapses, a process essential for sensory processing, learning and memory. However, little is known about how other forms of neuronal activity shape synaptic inputs. By using optogenetic activation of individual hippocampal CA1 pyramidal cells to drive action potential generation independently of synaptic inputs, we show that spiking activity induced structural changes in both inhibitory and excitatory synapses of the stimulated cells. I will present data to show that spiking activity induced by brief optogenetic activation causes cell autonomous changes in both synapse structure and function that lead to changes in the excitation/inhibition balance of the stimulated neurons.

Publications Nikonenko I, Nikonenko AG, Mendez P, Michurina T, Enikolopov G, Muller D. Nitric oxide mediates local activity‐dependent synaptic network development.

PNAS 2013 in press.

Mendez P, Pazienti A, Szabo G, Bacci A. Direct alteration of a specific inhibitory circuit of the hippocampus by antidepressants. J Neurosci. 2012 Nov 21;32(47):16616‐28 Mendez P, Garcia‐Segura LM, Muller D. Estradiol promotes spine growth and synapse formation without affecting pre‐established networks. Hippocampus.

2011 Dec;21(12):1263‐7.

Mendez P, De Roo M, Poglia L, Klauser P, Muller D. N‐cadherin mediates plasticity‐induced long‐term spine stabilization. J Cell Biol. 2010 May 3;189(3):589‐600

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Shira Knafo Biophysics Unit, UPV/EHU‐CSIC

Molecular blockade of synaptic depression prevents A‐induced cognitive decay It is believed that dyshomeostasis of amyloid‐ peptide (A) is responsible for synaptic malfunctions leading to a range of cognitive impairments from mild to full‐blown dementia in Alzheimer’s disease. At the synaptic level, A appears to skew synaptic plasticity events towards depression. We show here that PTEN is an obligatory mediator of A‐induced synaptic depression and LTP impairment.

In fact, A engages PTEN in a similar fashion as during NMDA receptor‐ dependent LTD, including the requirement for PDZ interactions. Moreover, we show that chronic PTEN inhibition protects Alzheimer’s model mice from learning and memory deficits. These results provide fundamental information regarding the synaptic actions of A, and may offer new mechanism‐based therapeutic approaches based on counteracting downstream A signaling, rather than lowering Aload.

Publications Knafo, S., Venero, C., Sánchez‐Puelles, C., Pereda‐Peréz, I., Franco, A., Sandi, C., Suárez, L. M., Solís, J. M., Alonso‐Nanclares, L., Martín, E. D., Merino‐Serrais, P., Borcel, E., Li, S., Chen, Y., Gonzalez‐Soriano, J., Berezin, V., Bock, E., DeFelipe, J., and Esteban, J. A. (2012) Facilitation of AMPA Receptor Synaptic Delivery as a Molecular Mechanism for Cognitive Enhancement. PLoS Biol 10, e1001262.

Jurado, S., and Knafo, S. (2012) Microscale AMPAR Reorganization and Dynamics of the Postsynaptic Density. J Neurosci 32, 7103‐7105 Arendt, K. L., Royo, M., Fernandez‐Monreal, M., Knafo, S., Petrok, C. N., Martens, J. R., and Esteban, J. A. (2010) PIP3 controls synaptic function by maintaining AMPA receptor clustering at the postsynaptic membrane. Nature Neuroscience 13, 36‐44

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Álvaro Llorente‐Berzal Universidad Complutense de Madrid

Long‐lasting effects of THC and/or MDMA in an animal model of adolescent drug consumption

My main interest is the study of the neurobehavioral changes induced by adolescent consumption of drugs of abuse. In this context, it is known that, in general, adolescents exhibit a myriad of behaviors that are “typical” of this stage of life, such as novelty seeking, increase of risk‐taking behaviors and a higher impulsivity. This characteristic behavioral profile contributes to explain why drug abuse typically starts during adolescence for most of the drugs known. To study this problem, we use animal models of adolescent drug exposure and perform a battery of different behavioral tests when animals reached the adulthood, together with hormonal, neurochemical and immunohistochemical analyses.

Publications Llorente‐Berzal A, Assis MA, Rubino T, Zamberletti E, Marco EM, Parolaro D, Ambrosio E, Viveros MP. Sex‐dependent changes in brain CB1R expression and functionality and immune CB2R expression as a consequence of maternal deprivation and adolescent cocaine exposure. Pharmacol Res. 2013, 74:23‐33.

Llorente‐Berzal A, Mela V, Borcel E, Valero M, López‐Gallardo M, Viveros MP, Marco EM. Neurobehavioural and metabolic long‐term consequences of neonatal maternal deprivation stress and adolescent olanzapine treatment in rats of both genders. Neuropharmacology 62(2012):1332‐1341 Mela V, Llorente‐Berzal A, Díaz F, Argente J, Viveros MP, Chowen JA. Maternal deprivation exacerbates the response to a high fat diet in a sexually dimorphic manner. Plos One. 2012. 7(11):e48915

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Gertrudis Perea Instituto Cajal, Madrid

Astrocyte activation modulates response selectivity of visual cortex neurons in vivo Astrocytes have important roles in brain homeostasis, such as buffering potassium ions and releasing molecules necessary for energy metabolism. We used optogenetic techniques to selectively manipulate astrocyte activity in layers 2/3 of primary visual cortex in mice by selective targetting with light‐ sensitive channelrhodopsin‐2 (ChR2) to evoke calcium responses. We simultaneously recorded the activity of neighbouring neurons in these cortical layers – in slices of visual cortex in vitro to examine synaptic influences of astrocytes on neurons, and in the intact visual cortex in vivo while presenting visual stimuli to the animals to examine the influence of astrocyte activation on tuned visual responses of neurons. Our data show that astrocytes regulate excitatory and inhibitory synaptic transmission in the visual cortex, which in turn drives changes in the excitation/inhibition balance in cortical networks and hence alters response features of visual cortex neurons.

Publications Perea G, Yang A, Boyden ES, Sur M. Optogenetic astrocyte activation modulates response selectivity of visual cortex neurons in vivo. Nat. Comm. (under 2nd review).

Chen N, Sugihara H, Sharma J, Perea G, Petravicz J, Le C, Sur M (2012) Nucleus basalis enabled stimulus specific plasticity in the visual cortex is mediated by astrocytes. Proc. Natl. Acad. Sci. USA. 109:E2832‐41 Navarrete M*, Perea G*, Fernandez de Sevilla D, Gómez‐Gonzalo M, Núñez A, Eduardo Martín ED, Araque A (2012). Astrocytes mediate in vivo cholinergic‐ induced synaptic plasticity. PLoS Biol. 10(2):e1001259.

Perea G, Araque A (2007). Astrocytes potentiate transmitter release at single hippocampal synapses. Science 317:1083‐1086

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Miguel Valencia CIMA, Navarra

Organizing information in the brain by means of cross‐frequency coupling mechanisms: Clinical and experimental scenarios My work involves the study of neural activity both in physiology and in the patho‐physiology of neurological and psychiatric diseases. My main goal is to understand the role of the basal ganglia and other subcortical structures oscillatory activity and cortical synchronization with major interest in Parkinson's Disease. Brain activity is composed by rhythms of different frequencies and localizations with activity coded in separated frequency bands (i.e. minimising cross‐frequency interference), thus allowing to process specific aspects of information. In this talk I'll review some examples from clinical and experimental scenarios where cross‐frequency coupling plays both physiological and pathophysiological roles during normal behaviour, disease and models of sleep.

Publications Valencia, M; Artieda, J; Bolam, JP; Mena‐Segovia, J. Dynamic interaction of spindles and gamma activity during cortical slow oscillations and its modulation by subcortical afferents. Plos One, 2013; 6(7): e21814).

Valencia, M; Lopez‐Azcarate, J; Nicolas, MJ; Alegre, M; Artieda, J. Dopaminergic modulation of the spectral characteristics in the rat brain oscillatory activity.

Chaos, Solitons & Fractals, 2012; 45(5): 619‐ 628.

Rodriguez‐Oroz, MC; Lopez‐Azcarate , J; Garcia‐Garcia, D; Alegre, M; Toledo, J; Valencia, M; Guridi, J; Artieda, J; Obeso, JA. Involvement of the subthalamic nucleus in impulse control disorders associated with Parkinson's disease. Brain, 2011; 134: 36 ‐49.

Lopez‐Azcarate , J; Tainta, M; Rodriguez‐Oroz, MC; Valencia, M Gonzalez, R; Guridi, J; Iriarte, J; Obeso, JA; Artieda, J; Alegre, M. Coupling between beta and high‐frequency activity in the human subthalamic nucleus may be a pathophysiological mechanism in Parkinson's Disease.

Journal of Neuroscience, 2010; 30: 6667‐ 6677 10

Bryan Strange Laboratory of Clinical Neuroscience, Centre for Biomedical Technology, UPM, Madrid

How salience modulates episodic memory in humans Bryan Strange currently holds an I3 programme Professorship at the Universidad Politécnica de Madrid, where he has recently set up the Laboratory of Clinical Neuroscience. He began his neuroscience training as an undergraduate in the synaptic plasticity laboratory of Graham Collingridge. He holds a medical degree from University College London and did his PhD in cognitive neuroscience at the Wellcome Department of Cognitive Neurology, Institute of Neurology, London, under Ray Dolan and Karl Friston. His research interests focus on the functions of the human medial temporal lobe. In particular, he investigates how the hippocampus processes novel or unexpected events, and how this facilitates human memory. He also works on the role of the amygdala in mediating enhanced memory for emotional stimuli. He uses a multi‐ disciplinary approach to study human memory, combining functional brain imaging techniques with patient lesion data, pharmacology, genetics and human intracranial recordings.

Publications Kroes MCW, Tendolkar I, van Wingen GA, van Waarde JA, Strange B, Fernández G (2014) An electroconvulsive therapy procedure impairs reconsolidation of emotional episodic memories in humans. Nature Neuroscience (in press).

Strange BA, Gartmann N, Brenninkmeyer J, Haaker J, Reif A, Kalisch R, Büchel C (2013) Dopamine receptor 4 promoter polymorphism modulates memory and neuronal responses to salience. Neuroimage 84C:922‐931.

Moratti S, Saugar C, Strange BA (2011) Prefrontal‐occipitoparietal coupling underlies late latency human neuronal responses to emotion. Journal of Neuroscience 31:17278‐86.

Strange BA, Dolan RJ (2004) Beta‐adrenergic modulation of emotional memory‐ evoked human amygdala and hippocampal responses. PNAS 101:11454‐11458

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Cristina Nombela University of Cambridge

Genetic variation of cognitive deficits and brain function in newly diagnosed Parkinson’s disease I am currently responsible for functional neuroimaging of a project to studying the incidence of cognitive impairments in Parkinson’s Disease, funded by the UK Parkinson's Disease Society. The project includes clinical and neuro‐ psychological assessment, genotyping, CSF analysis, sleep, fMRI, PET and brain tissue studies. Furthermore, I am implicated in other projects such as the study of PD impulsiveness, music therapy, clinical trials in drug treatments for cognitive symptoms in PD and the description of executive functions in parkinsonism.

Publications Nombela C, Rae CL, Owen AM, Grahn JL, Rowe J. (2013) How beneficial is rhythm stimulation for improving motor features in Parkinson’s disease? J Neurol May; 260(5): 1404–1405.

Nombela C, Pedreño‐Molina JL, Molina‐Vilaplana J, Ros‐Bernal F, Barcia C, López‐Coronado J, Herrero MT. (2012). Motor perseveration during a precision motor task in parkinsonian patients: the light object pattern. Hum Mov Sci 31:730‐42.

Nombela C, Bustillo PJ, Castell PF, Sanchez L, García Medina V, Herrero MT. (2011). Cognitive rehabilitation in Parkinson’s disease: evidence from neuroimaging. Front Neurol 2:82.

Barcia C, Ros F, Carrillo MA, Aguado‐Llera D, Ros CM, Gómez A, Nombela C, de Pablos V, Fernández‐Villalba E & Herrero MT. (2009). Inflammatory response in Parkinsonism. J Neural Transm Suppl 73:245‐52

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Who we are The Instituto Cajal is a neuroscience research center assigned to the Spanish Research Council (CSIC). The Cajal institute is the oldest neurobiology research center in Spain. Along its more than 100 years of existence, renowned scientists and professionals have spread worldwide and contributed to the remarkable advancement of neurobiology. Today, the institute is prepared to confront the future challenges and to maintain the leading role in neurobiological research in Spain, always keeping in mind that the final destination of knowledge is the wellbeing of the society.

Contact Us You can reach the institute by metro (Línea 6, República Argentica and Línea 9, Concha Espina) or by bus (lines C ‐ 7 ‐ 16 ‐ 19 ‐ 29 ‐ 43 ‐ 51 ‐ 52 – 120) Ave. Doctor Arce, 37 Madrid 28002. Spain Phone: 91 585 4750 Email: protocol@cajal.csic.es Web: www.cajal.csic.es

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