Synapse Biology

Ana Luísa Carvalho

PhD, Group Leader

Memories, thoughts and behavior are encoded in changes in the strength of synaptic communication. These changes constitute the cellular and molecular basis of information processing underlying brain function. However, the functional transformations used by synapses to encode and process information are still poorly understood. We are interested in the cellular and molecular mechanisms of synaptic function and plasticity, and in how synaptic dysfunction underlies neuropsychiatric and neurodegenerative disorders.

We use a combination of techniques like primary cultures of dissociated neurons and brain slices, biochemistry, molecular and cellular biology, mouse molecular genetics, electrophysiology and behavior analysis to address the role of molecular players and of neuromodulatory processes that regulate neurotransmitter receptors and synaptic function and plasticity.

This fundamental research has strong implications to cognitive disorders, since genetic variants in multiple synaptic proteins are linked to intellectual disability, schizophrenia and autism spectrum disorders, and age-associated neurodegenerative disorders are at their initial stages originated by defects in synaptic transmission. We focus on disease-related alterations in synaptic function, either genetic, triggered by experience or by antibodies produced by autoimmune synaptic encephalitis patients, to understand how synaptic dysfunction underlies disease pathogenesis. Our cellular and molecular studies and the animal models that we are generating can also contribute to the rational development of therapies for these diseases.

Group Members

Group Members

Group members are: Ana Luisa Carvalho (PhD, Group Leader), Paulo Pinheiro (PhD), Joana Ferreira (PhD), Luís Ribeiro (PhD), Ester Coutinho (MD, PhD), Sandra Santos (MD, PhD), Ângela Inácio (PhD), Jeannette Schmidt (PhD), Marina Rodrigues (PhD student), Beatriz Rodrigues (PhD student), Débora Serrenho (PhD student), Nuno Beltrão (PhD student), Orsolya Antal (PhD student), Sara Ribau (MSc student), Giovanna Bruno (MSc student), Alejandra Nunez Torres (Laboratory Technician).

Selected Publications

Caldeira GL, Inácio AS, Beltrão N, Barreto CAV, Rodrigues MV, Rondão T, Macedo R, Gouveia RP, Edfawy M, Guedes J, Cruz B, Louros SR, Moreira IS, Peça J, Carvalho AL (2022) Aberrant hippocampal transmission and behavior in mice with a stargazin mutation linked to intellectual disability. Molecular Psychiatry, https://doi.org/10.1038/s41380-022-01487-w

Ribeiro L.F., Catarino T., Carvalho M., Cortes L., Santos SD, Opazo P., Ribeiro L.R. Oliveiros B., Choquet D., Esteban J.A., Peça J., Carvalho A.L. (2021) Ligand-independent activity of the ghrelin receptor modulates AMPA receptors trafficking and supports memory formation. Sci. Signal. 14, eabb1953. DOI: 10.1126/scisignal.abb1953 (Cover story)

Carvalhais LG, Martinho VC, Ferreiro E and Pinheiro PS, Unraveling the Nanoscopic Organization and Function of Central Mammalian Presynapses With Super-Resolution Microscopy, Front. Neurosci., 08 January 2021 | https://doi.org/10.3389/fnins.2020.578409

Lima Caldeira G., Peca J., Carvalho A.L. (2019) New insights on synaptic dysfunction in neuropsychiatric disorders. Curr Opin Neurobiol 57, 62-70. DOI: 10.1016/j.conb.2019.01.004

Silva M.M., Rodrigues B., Fernandes J., Santos S.D., Carreto L., Santos M.A.S., Pinheiro P., Carvalho A.L. (2019) MicroRNA-186-5p controls GluA2 surface expression and synaptic scaling in hippocampal neurons. PNAS 116(12), 5727-5736. DOI: 10.1073/pnas.1900338116

Fernandes D., Santos S.D., Coutinho, E., Whitt J.L., Rondão T., Leite M.I., Buckley C., Lee H.K., Carvalho A.L. (2019) Disrupted AMPA receptor function upon genetic or antibody-mediated loss of autism-associated CASPR2. Cerebral Cortex 29:4919-4931. DOI: 10.1093/cercor/bhz032

Kellermayer B., Ferreira J.S., Dupuis J., Levet F., Grillo-Bosch D., Bard L., Linares-Loyez J., Bouchet D., Choquet D., Rusakov D.A., Bon P., Sibarita J.B., Cognet L., Sainlos M., Carvalho A.L., Groc L. (2018) Differential Nanoscale Topography and Functional Role of GluN2-NMDA Receptor Subtypes at Glutamatergic Synapses. Neuron 100, 106-119 e107. DOI: 10.1016/j.neuron.2018.09.012

Vieira M.M., Schmidt, J., Ferreira, J. S., She, K., Oku, S., Mele, M., Santos, A. E., Duarte, C. B., Craig, A. M., and Carvalho, A. L. (2016) Multiple domains in the C-terminus of NMDA receptor GluN2B subunit contribute to neuronal death following in vitro ischemia. Neurobiol Dis 89, 223-234.

Matos, C. A., Nobrega, C., Louros, S. R., Almeida, B., Ferreiro, E., Valero, J., Pereira de Almeida, L., Macedo-Ribeiro, S., and Carvalho, A. L. (2016) Ataxin-3 phosphorylation decreases neuronal defects in spinocerebellar ataxia type 3 models. J Cell Biol 212, 465-480. DOI: 10.1083/jcb.201506025

Ferreira, J. S., Schmidt, J., Rio, P., Aguas, R., Rooyakkers, A., Li, K. W., Smit, A. B., Craig, A. M., and Carvalho, A. L. (2015) GluN2B Containing NMDA Receptors Regulate AMPA Receptor Traffic through Anchoring of the Synaptic Proteasome. J Neurosci 35, 8462-8479.

Selected Projects

Syn2Psy: Synaptic Dysfunction in Neuropsychiatric Disorders, ITN H2020 EC, PI: Ana Luisa Carvalho

MStar: Potassium channel dysfunction in models of neurodevelopmental disorders, laCaixa Foundation/FCT, PI: Ana Luisa Carvalho

microSTRESS: Regulation of prefrontal cortical synaptic function and behavior by chronic stress-induced microRNA-186-5p, laCaixa Foundation/FCT, PI: Paulo Pinheiro

Uncovering the molecular machinery responsible for cargo sorting in neuronal polarization, FCT, PI: Luís Ribeiro (PTDC/BIA-CEL/2286/2020)

A New Trans-Synaptic Bridge: Functional characterization of the NMDA receptor-Neurexin-2 interaction, IBRO Return Home Fellowship 2021, PI: Joana Ferreira

The study of the novel NMDA receptor-Neurexin-2 interaction and potential role in schizophrenia, 2021 NARSAD Young Investigator Grant, PI: Joana Ferreira

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