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Sebastião, Ana
Lab

Neuronal Communication & Synaptopathies

Neurological and neuropsychiatric diseases constitute an overwhelming social and economic load, with predicted exponential increase in the near future due to ageing, drug abuse, traumatic life styles. There is growing awareness that a common feature in these diseases is a dysfunction of neuronal communication, that is to say, a synaptic dysfunction. The major focus of the Unit is to evaluate how synapses are modulated and how these processes are altered by disease states or reverted by putative therapeutics.

Under specific focus at the moment are synaptic dysfunction in developmental epilepsy pathologies such as Rett syndrome, synaptic circuitry remodeling after stroke and seizures, synaptic reorganization after chronic drug abuse, functional alterations of synaptic function at the onset of neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer’s disease.

 

  • Research Areas

    The Unit is constituted by balanced multidisciplinary team organized in five groups according to their specific research topics, as follows:

    • Modulation of the tripartite synapse. This group aims to elucidate pre- post and glial mechanisms involved in the control of the delicate balance between neuronal inhibition and excitation and its implications for synaptic plasticity. Following this research line, the group evaluates the synaptic and behavioural (learning, memory, anxiety, depression) consequences of long term manipulation of endogenous modulator (adenosine and cannabinoids) signaling.
    • Motor neuron. This group aims to elucidate the fine tune control of motor neuron activity under normal and pathological conditions, as amyotrophic lateral sclerosis (ALS).
    • Neurotrophic factors. This group aims to understand the causes and mechanisms of neuronal dysfunction caused by the lack of trophic support to synapse formation/ maturation/ protection. The implications for developmental epilepsies, ageing and Alzheimer’s disease are under focus.
    • Neurobiology of inflammation - interplay with epilepsy. This group aims to understand the relationship between inflammation and epilepsy to identify key points in the inflammatory cascade that may constitute as therapeutic targets to prevent epileptogenesis.
    • Control of post-natal neurogenesis and oligodendrogenesis. The group aims to understand how post-natal formation of new neurons and oligodendrocytes is regulated and its implications for the control of neuronal diseases as multiple sclerosis.
  • Research Team

    • Ongoing Research Projects

      2016/2018 (accepted for funding in 2015) Twinning action (iMM, University of Lancaster, University of Rome, University of Eastern Finland) – “Neurologic and Psychiatric Disorders: from synapses to networks” (SynaNet). H2020. Amount: 525,438€.

      2016/2018 (accepted for funding in 2015) “Synaptic, mechanisms involved in the brain cannabinoid actions and their modulation by adenosine receptors: implications for memory and mood control” PTDC/DTP-FTO/3346/2014. PI: Ana M Sebastião. Collaboration with Atilla Kofalvi, University of Coimbra. Amount: Total – 199,800€; iMM – 188,800€.

      2016/2018 (accepted for funding in 2015) “Optogenetic dissection of neural circuits controlling adiposity” PTDC/BIM-MET/3750/2014, Project PI: Ana Domingos, Instituto Gulbenkian de Ciência.  PI at iMM: Ana M Sebastião. Amount iMM: 19,800€.

      2016/2018 (accepted for funding in 2015) “Relationship between adenosine and chromosomal instability: a new perspective to understand the oncogenic mechanism in glioblastoma”, Project PI: António Francisco Cascalheira, Universidade da Beira Interior. PI at iMM: Ana M Sebastião. Amount iMM: 25,000€

      2013/2016 “Cannabinoid/adenosine cross talk to modulate synaptic plasticity”, PI: Ana M Sebastião. Agency: Cardlane Ltd.. Reference: PhD project Armando Cruz. Amount: 80.984,00 €.

      2013/2015 “Neurophysiological mechanisms of aging: novel view of old concepts”, PI: Maria José Diógenes. Agency: Fundação Bial. Reference: Bial fellowship programme 57/12. Amount: 49,000€.

      2014/2015 “Rett Syndrome”, PI: Maria José Diógenes. Agency: Fundació Privada Per La Receca Il a Doència. Reference: Rett Syndrome. Amount: 6000.00€.

      2014/2015 “Adenosine receptors: new pharmacological targets for Rett syndrome treatment”, PI: Maria José Diógenes. Agency: Fundação para a Ciência e a Tecnologia, IP. Reference: EXPL/BIM-MEC/0009/2013. Amount: 50,000€.

      2015/2016 Bridge Grant 2015, PI: Ana M Sebastião. Agency: Fundação para a Ciência e a Tecnologia, IP. Reference: BridgeGrant2015 ASebastiao. Amount: 15,000€.

      2014/2016 “Targeting selected synapses to develop new antiepileptic drugs with minimal side effects”. In collaboration with Ken Jackobson, NIH (Bethesda, USA). PI: Ana M Sebastião.

      2014/2016 “Adenosine kinase deficiency and epilepsy: synaptic characterization of adenosine signaling”. In collaboration with Detlev Boison (Portland, USA).

      2010/2016 “Amyloid beta peptide-induced toxicity: impact on hippocampal function”, PI: Maria José Diógenes.

      2013/2016 “Neurobiology of inflammation – interplay with epilepsy”, PI: Cláudia Valente.

      2014/2016 "Glycine function in astrocyte calcium signaling”, PI: Cláudia Valente.

      2014/2015 "Microglial expression of SIRT2: consequences for LTP”. Funded by GAPIC/FMUL. PI: Maria José Diógenes, in collaboration with Teresa Pais, CEDOC. Amount: 650,00€.

      2013/2016 “Synaptic activity modulation by Erythropoietin”, PI: Raquel Dias.

      2013/2017 “Astrocytic influence of BDNF actions at the hippocampus”, PI: Sandra Vaz.

      2015/2016 “Hebbian Plasticity-driven changes of synaptic homeostasis in Alzheimer’s Disease”, Financed by Bolsas Gulbenkian/FMUL, PI: Maria José Diógenes. Amount: 2.500€.

      2012/2015 “Astrocytic calcium signalling modulation by purines”, PI: Sandra Vaz.

      2013/2016 “Modulatory role of adenosine and canabinoids in oligodendrogenesis and neurogenesis derived from neural stem/progenitor cells of the subventricular zone", PI: Sara Xapelli.

      2015/2018 “Adenosine and VEGF modulatory role in amyotrophic lateral sclerosis (ALS)”, PI: Ana Sebastião and JA Ribeiro.

    • Prizes

    • Selected Publications

      30 peer reviewed publications (out of near 90) by Unit members since 2004

      1. Ribeiro FF, RNeves-Tomé R, Assaife-Lopes N, Santos TE, Silva RFM, Brites D, Ribeiro JA, Sousa MM, Sebastião AM (2015) Axonal elongation and dendritic branching is enhanced by adenosine A2A receptors activation in cerebral cortical neurons. Brain Struct & Func (in the press).
      2. Nascimento F, Sebastião AM, Ribeiro JA. (2015) Presymptomatic and symptomatic ALS SOD1(G93A) mice differ in adenosine A1 and A 2A receptor-mediated tonic modulation of neuromuscular transmission. Purinergic Signal. (in the press)
      3. Jerónimo-Santos A, Fonseca-Gomes J, Guimarães DA, Tanqueiro SR, Ramalho RM, Ribeiro JA, Sebastião AM, Diógenes MJ (2015) Brain-derived neurotrophic factor mediates neuroprotection against Aβ-induced toxicity through a mechanism independent on adenosine 2A receptor activation. Growth Factors 12:1-11.
      4. Aroeira RI, Sebastião AM and Valente CA (2015). BDNF, via truncated TrkB receptor, modulates GlyT1 and GlyT2 in astrocytes. Glia. 63(12):2181-97.
      5. Rombo DM, Dias RB, Duarte ST, Ribeiro JA, Lamsa KP, Sebastião AM (2015). Adenosine A1 receptor suppresses Tonic GABAA receptor currents in hippocampal pyramidal cells and in a defined subpopulation of interneurons. Cereb Cortex. 25(9):3107-21.
      6. Pousinha PA, Correia AM, Sebastião AM, Ribeiro JA (2015) The giant miniature endplate potentials frequency is increased in aged rats. Neurosci Lett. 584C:224-229 (ePub October 2014).
      7. Félix-Oliveira A, Dias RB, Colino-Oliveira M, Rombo DM, Sebastião AM (2014) Homeostatic Plasticity induced by Brief Activity Deprivation Enhances Long-Term Potentiation in the Mature Rat Hippocampus. J Neurophysiol 112:3012-1022.
      8. Jacob JP, Vaz SH, Ribeiro JA, Sebastião AM (2014) P2Y1 receptor inhibits GABA transport through a calcium signalling-dependent mechanism in rat cortical astrocytes. Glia 62:1211-1226.
      9. Diógenes MJ, Neves-Tomé R, Fucile S, Martinello K, Scianni M, Theofilas P, Lopatár J, Ribeiro JA, Maggi L, Frenguelli BG, Limatola C, Boison D, Sebastião AM (2014). Homeostatic Control of Synaptic Activity by Endogenous Adenosine is Mediated by Adenosine Kinase. Cereb Cortex.24:67-80.
      10. Jerónimo-Santos A, Vaz SH, Parreira S, Rapaz-Lérias S, Caetano AP, Buée-Scherrer V, Castrén E, Valente CA, Blum D, Sebastião AM, Diógenes MJ (2014) Dysregulation of TrkB Receptors and BDNF Function by Amyloid-β Peptide is Mediated by Calpain. Cereb Cortex 25(9):3107-21.
      11. Rodrigues TM, Jerónimo-Santos A, Sebastião AM, Diógenes MJ (2014) Adenosine A2A Receptors as novel upstream regulators of BDNF-mediated attenuation of hippocampal Long-Term Depression (LTD). Neuropharmacology 79:389-398.
      12. Assaife-LopesN, Sousa VC, Pereira DB, RibeiroJA, Sebastião AM (2014) Regulation of TrkB receptor translocation to lipid rafts by adenosine A2A receptors and its functional implications for BDNF-induced regulation of synaptic plasticity. Purinergic Signalling 10:251-267.
      13. Jerónimo-Santos A, Batalha VL, Müller CE, Baqi Y, Sebastião AM, Lopes LV, Diógenes MJ. (2014) Impact of in vivo chronic blockade of adenosine A2A receptors on the BDNF-mediated facilitation of LTP. Neuropharmacology 83:99-106.
      14. Pires M, Raischel F, Vaz SH, Cruz-Silva A, Sebastião AM, Lind PG (2014) Modeling the functional network of primary intercellular Ca2+ wave propagation in astrocytes and its application to study drug effects, Journal of Theoretical Biology 356C:201-212.
      15. Nascimento, F, Pousinha PA, Marçal-Correia A; Gomes R, Sebastião AM, Ribeiro JA (2014) "Adenosine A2A receptors activation facilitates neuromuscular transmission in the pre-symptomatic phase of the SOD1(G93A) ALS mice, but not in the symptomatic phase". PLoS ONE 9(8):e104081
      16. Rocha, MC, Pousinha PA, Correia AM, Sebastião AM, Ribeiro JA (2013) Early changes of neuromuscular transmission in the SOD1(G93A) mice model of ALS start long before motor symptoms onset. PLOS ONE, Sep 5;8(9):e73846. doi: 10.1371/journal.pone.0073846. eCollection
      17. Aroeira RI, Sebastião AM, Valente CA (2014) GlyT1 and GlyT2 in brain astrocytes: expression, distribution and function. Brain Struct Funct 219:817-30.  
      18. Dias RB, Rombo DM, Ribeiro JA, Henley JM, Sebastião AM (2013) Adenosine: setting the stage for plasticity. Trends in Neuroscience 36:248-257.
      19. Cristóvão-Ferreira S, Navarro G, Brugarolas M, Pérez-Capote K, Vaz SH, Fattorini G, Conti F, Lluis C, Ribeiro JA, Mccormick PJ, Casadó V, Franco R, Sebastião AM (2013) A1R-A2AR heteromers coupled to Gs and Gi/0 proteins modulate GABA transport into astrocytes. Purinergic Signalling 9:433-449.
      20. Dias RB, Rombo DM, Ribeiro JA, Sebastião AM (2013) Ischemia-induced synaptic plasticity drives sustained expression of calcium-permeable AMPA receptors in the hippocampus. Neuropharmacology  65:114-122.
      21. Pousinha PA, Correia AM, Sebastião AM and Ribeiro JA. (2012). Neuromuscular transmission modulation by adenosine upon aging. Neurobiol Aging33: 2869-2880.
      22. Dias RB, Ribeiro JA, Sebastião AM (2012). Enhancement of AMPA currents and GluR1 membrane expression through PKA- coupled adenosine A2A receptors. Hippocampus 22: 276-291.
      23. Vaz SH, Jorgensen TN, Cristovão-Ferreira S, Duflot S, Ribeiro JA, Gether U, Sebastião AM (2011) Brain-derived neurotrophic factor (BDNF) enhances GABA transport by modulating the trafficking of GABA transporter-1 (GAT-1) from the plasma membrane of rat cortical astrocytes. J Biol Chem 286:40464-4076.
      24. Sousa VC, Assaife-Lopes N, Ribeiro JA, Pratt JA, Brett RR, Sebastião AM (2011) Regulation of hippocampal cannabinoid CB1 receptor actions by adenosine A1 receptors and chronic caffeine administration: implications for the effects of ∆9-tetrahydrocannabinol on spatial memory. Neuropsychopharmacology 36, 472-487.
      25. Moreno* E, Vaz* SH, Cai NS, Ferrada C, Quiroz C, Barodia SK, Kabbani N, Canela EI, McCormick PJ, Luis C, Franco R, Ribeiro JA, Sebastião AM*, Ferré S* (2011) Dopamine-Galanin Receptor Heteromers Modulate Cholinergic Neurotransmission in the Rat Ventral Hippocampus. J Neurosci. 31:7412-7423. *Co-first authors and co-senior authors.
      26. Diógenes MJ, Costenla AR, Lopes LV, Jerónimo-Santos A, Sousa VC, Fontinha BM, Ribeiro JA, Sebastião AM (2011) Enhancement of LTP in aged rats is dependent on endogenous BDNF. Neuropsychopharmacology 36:1823-1836.
      27. Kemppainen S, Rantamäki T, Jerónimo-Santos A, Lavasseurd G, Autio H, Karpova N, Kärkkäinena E, Stavéna S, Miranda HV, Outeiro TF, Diógenes MJ, Laroched S, Davis S, Sebastião AM, Castrén E, Tanila H (2011) Impaired TrkB receptor signaling contributes to memory impairment in APP/PS1 mice. Neurobiol Aging. 33(6):1122.e23-39.
      28. Aroeira RI, Ribeiro JA, Sebastião AM, Valente CA. (2011) Age-related changes of glycine receptor at the rat hippocampus: from the embryo to the adult. J Neurochem. 118:339-53.
      29. Fernandes CC, Pinto-Duarte A, Ribeiro JA, Sebastião AM (2008) Postsynaptic action of brain-derived neurotrophic factor attenuates alpha7 nicotinic acetylcholine receptor-mediated  responses in  hippocampal interneurons. J Neurosci. 28:5611-5618.
      30. Diógenes MJ, Fernandes CC, Sebastião AM, Ribeiro JÁ (2004) Activation of adenosine A2A receptor facilitates BDNF modulation of synaptic transmission in hippocampal slices. J. Neurosci. 24: 2905-2913.

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