Areas of focus

The activity of neuronal circuits under physiological conditions is tightly regulated, by mechanisms acting at pre- and post-synaptic levels. Changes in neuronal connectivity, either strengthening or weakening the interaction between neurons, are associated with many disorders of the nervous system. Research in this unit focuses on 1) the mechanisms of regulation of the synaptic function by neurotrophins, which account for their role in long-term synaptic plasticity and in learning and memory formation, and how dysregulation of these processes contribute to several diseases of the nervous system; 2) the alterations in proteostasis coupled neuronal death in brain ischemia; 3) how dysregulation of GABAergic synapses contribute to the increased neuronal excitability in epilepsy; and 4) the new molecular players underlying neuronal architecture changes in intellectual disability, such as Rett syndrome. The group uses standard biochemistry, cellular and molecular biology, electrophysiology and behavioural approaches, complemented with in vitro (neuronal cultures) and in vivo models of disease, to address these questions.
 

Regulation of glutamatergic synapses by BDNF in synaptic plasticity and in disease 
PI: Carlos B. Duarte

NT3-TrkC signaling in the regulation of fear memories 
PI: Mónica Santos

New molecular players in Rett syndrome (RTT) pathophysiology 
PI: Mónica Santos

Molecular mechanisms of epileptogenesis: the role of GABAergic synapses 
PI: Miranda Mele

Excitotoxic injury in brain ischemia: the role of dysregulation of the ubiquitin-proteasome system 
PI: Carlos B. Duarte

Carlos B. Duarte Group Leader Full Professor, UC   Ph. +351 304502910		Mónica Santos   PhD Researcher   Ph. +351 304502914	Emília P. Duarte   PhD Researcher, UC Ph. +351 239104473		Rui O. Costa   PhD Researcher Ph. +351 304502914
Miranda Mele   PhD Researcher   Tel: +351 304502914		Ivan Salazar   PhD Researcher Ph. +351 304502917	Filipe V. Duarte   PhD Researcher Tel: +351 304502914
Pasqualino De Luca   PhD Student Ph. +351 304502917		Elisa Corti Collaboration PhD Student Ph. +351 304502917	Elena Rodriguez Collaboration PhD Student Ph. +351 304502917
Gianluca Masella   MSc Student   Ph. +351 304502917		Chiara Corrado   MSc Student   Ph. +351 304502917	Giorgio Belperio   MSc Student   Ph. +351 304502917

Alumni

Collaborations

Lorella Canzoniero
University of Sannio, Benevento, Italy

Andrea Barberis
Italian Institute of Technology, Genoa, Italy

Clive Bramham
University of Bergen, Norway

Ana M. Sebastião
IMM, University of Lisbon, Portugal

Maria João Saraiva
I3S, University of Porto, Portugal

Ana Paula Pego
I3S, University of Porto, Portugal

Ramiro Almeida
University of Aveiro, Aveiro, Portugal

Ka Wan Li
Neuroscience Campus Amsterdam, The Netherlands

Carmen Agustin-Pavòn
University of Valencia, Spain

Oliver Stork
Otto-von-Guericke University, Magdeburg, Germany

Funding

Fundação para a Ciência e a Tecnologia
FCT, Portugal

National Multiple Sclerosis Society
USA

Marie Sklodowsska-Curie Actions
European Commission

BIAL Foundation
Portugal

FinRett
Spain

Selected Publications

P Afonso, P De Luca, RS Carvalho, L Cortes, P Pinheiro, B Oliveiros, RD Almeida, M Mele, CB Duarte (2019) BDNF increases synaptic NMDA receptor abundance by enhancing the local translation of Pyk2 in cultured hippocampal neurons. Science Signal 12: eaav3577.
 

- Martínez-Rodríguez E, Martín-Sánchez A, Coviello S, Foiani C, Kul E, Stork O, Martínez-García F,  Nacher J, Lanuza E, Santos M*, Agustín-Pavón C*. Lack of MeCP2 leads to region-specific increase of doublecortin in the olfactory system. Brain Struct & Function 2019 224(4): 1647-1658. * joint last authors
 

G Leal, D Comprido, P de Luca, E Morais, L Rodrigues, M Mele, AR Santos, RO Costa, MJ Pinto, S Patil, B Berentsen, P Afonso, L Carreto, KW Li, P Pinheiro, RD Almeida, MAS Santos, CR Bramham, CB Duarte (2017) The RNA binding protein hnRNP K mediates the effect of BDNF on dendritic mRNA metabolism and regulates synaptic NMDA receptors in hippocampal neurons. eNeuro 4: ENEURO.0268-17.2017.

M Mele, MC Aspromonte, CB Duarte (2017) Downregulation of GABA_A receptor recycling mediated by HAP1 contributes to neuronal death in In vitro brain ischemia. Mol Neurobiol. 54:45-57.
 

- Castro H, Kul E, Buijsen RAM, Severijnen LWFM, Willemsen R, Hukema RK, Stork O*, Santos M*. Selective rescue of heightened anxiety but not gait ataxia in a premutation 90CGG mouse model of Fragile X-associated tremor/ataxia syndrome. Hum Mol Genet 2017 1;26(11):2133-2145. * joint last authors.
 

JT Costa, M. Mele, M.S. Baptista, J.R. Gomes, K. Ruscher, R.J. Nobre, L.P. de Almeida, T. Wieloch, CB Duarte (2016) Gephyrin Cleavage in In Vitro Brain Ischemia Decreases GABA_A Receptor Clustering and Contributes to Neuronal Death. Mol Neurobiol 53, 3513-3527
 

- D’Amico D, Gener T, de Lagrán MM, Sanchez-Vives MV, Dierssen M*, Santos M*. Infralimbic neurotrophin-3 infusion rescues fear extinction impairment in a mouse model of pathological fear. Neuropsychopharmacology 2016 42 (2): 462-472. * joint last authors.
 

M Curcio, IL Salazar, M Mele, LM Canzoniero, CB Duarte (2016) Calpains and neuronal damage in the ischemic brain: the swiss knife in synaptic injury. Prog Neurobiol  143:1-35.
 

A.R. Santos, M. Mele, S.H. Vaz, B. Kellermayer, M. Grimaldi, M. Colino-Oliveira, D.M. Rombo, D Comprido, A.M. Sebastião, CB Duarte (2015) Differential role of the proteasome in the early- and late-phases of BDNF-induced facilitation of LTP. J Neurosci 35, 3319-3329.
 

M. Curcio, I.L. Salazar, A.R. Inácio, E.P. Duarte, L.M.T. Canzoniero, CB Duarte (2015) Brain ischemia downregulates the neuroprotective GDNF-Ret signaling by a calpain-dependent mechanism in cultured hippocampal neurons. Cell Death Dis 6, e1645.
 

J.R. Gomes, J.T. Costa, C.V. Melo, F. Felizzi, P. Monteiro, M.J. Pinto, A.R. Inacio, T. Wieloch, R.D. Almeida, M. Graos, CB Duarte (2012) Excitotoxicity downregulates TrkB.FL signaling and upregulates the neuroprotective truncated TrkB receptors in cultured hippocampal and striatal neurons. J Neurosci 32:4610-4622.