Neurotrophin Signaling and Synaptic (Dys)function

Carlos B Duarte

PhD, Group Leader

Neurotrophins play numerous roles in the nervous system, including the regulation of neuronal development, long-term modulation of synaptic transmission and in neuronal survival and neuroprotection under several different injury conditions. These effects are mediated by activation of specific receptors with tyrosine kinase activity, which are coupled to the activation of several parallel intracellular signaling cascades. Some of these intracellular pathways regulate the translation machinery, thereby controlling local protein synthesis using transcripts transported along the dendrites in RNA granules. Alterations in these signaling mechanisms have been associated with the dysregulation of local synthesis of proteins and are involved in various disorders of the central and peripheral nervous systems.

This group focuses on:

  1. Understanding the molecular mechanisms induced locally by neurotrophins to regulate neuronal development and synaptic plasticity, which may account for their effects in learning and memory formation;
  2. The alterations in neurotrophin signaling and in proteostasis in diseases of the nervous system characterized by excessive excitatory activity (e.g. brain ischemia and epilepsy);
  3. How an impairment in neurotrophin signaling is coupled to synaptic dysfunction in some neuropsychiatric disorders.

The effect of neurotrophins is mainly studied on glutamatergic synapses, but how the resulting changes in neuronal excitability affect inhibitory neurotransmission is also investigated. To address these questions the group uses neuronal cell cultures and animal models of disease, in addition to a wide range of experimental tools, including biochemical approaches, together with cellular and molecular biology and electrophysiology techniques.

Group Members

Group memberes are: Carlos B Duarte (PhD, Group Leader), Diogo Tomé, Emilia Duarte (PhD), Ivan Lalanda Salazar (PhD), Luís Martins, Margarida Caldeira (PhD), Miranda Mele (PhD), Monica Santos (PhD), Pasqualino De Luca, Rafael Carvalho, Rui O Costa (PhD).

Selected Publications

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, Duarte CB. (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(6) e0268-17.

Castro H, Kul E, Buijsen RAM, Severijnen LWFM, Willemsen R, Hukema RK, Stork O, Santos M. (2017) 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. 26, 2133-2145.

JT Costa, M Mele, MS Baptista, JR Gomes, K Ruscher, RJ Nobre, LP de Almeida, T Wieloch, CB Duarte (2016) Gephyrin Cleavage in In Vitro Brain Ischemia Decreases GABAA Receptor Clustering and Contributes to Neuronal Death. Mol Neurobiol. 53, 3513-3527.

M Curcio, IL Salazar, AR Inácio, EP Duarte, LM 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.

AR Santos, M Mele, SH Vaz, B Kellermayer, M Grimaldi, M Colino-Oliveira, DM Rombo, D Comprido, AM 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.

Selected Projects

Novel cerebrospinal fluid and serum biomarkers for Multiple Sclerosis, Grant # RG-1601-07502, National Multiple Sclerosis Society, USA. (2016 – 2019). PI: Carlos Duarte

BDNF-induced alterations in the synaptic proteome and neuronal excitability in the pilocarpine model of temporal lobel epilepsy, COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation, FCT – Fundação para a Ciência e a Tecnologia, Portugal (2018-2021). PI: Carlos Duarte

Targeting the K+-Cl- cotransporter (KCC2) to maintain GABAergic neurotransmission: a novel therapeutic strategy for epilepsy, COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation, FCT – Fundação para a Ciência e a Tecnologia, Portugal (2018-2021). PI: Miranda Mele

Biodegradable dendrimers for targeted neuroprotective therapies in stroke, PTDC/CTM-NAN/3547/2014, Funded by FCT, Portugal (2016 – 2019). PI at CNC: Carlos B. Duarte