Weighing an average of 1.3 kilograms, the human brain is a marvel of nature. Our brain has evolved to provide us with amazing sensory, emotional, memory and cognitive abilities. From an evolutionary perspective, it has even been argued that the most critical changes imposed on the human brain are directly linked to refinements in the “social brain”. Mammals use several brain regions to fully process and respond to social environments – from the senses, to memory of others and emotional centers, many regions are needed for the expression of social behaviors. As a consequence of this complexity, neuropsychiatric and neurodevelopmental disorders share impairments in social behaviors.

Our research aims to understand at the molecular, cellular and circuit levels, how genetics, environment and gene-environment interactions control neuronal circuit function in health and disease, with a specific focus on neurodevelopmental disorders and social behaviors. To achieve this goal, we use a combination of molecular genetics, behavior, electrophysiology and optogenetics techniques. Specifically, we develop both mouse and human cell-based models of disease to understand both the genetic and environmental components of neurodevelopmental diseases, with a special focus on the mechanisms that underlie behaviors reminiscent of these conditions.

Keywords

Autism spectrum disorder

Neurodevelopment

Models of disease

Behavior

Electrophysiology

Research Lines

1 - Synaptic plasticity and autism

2 - Early life stress and brain wiring

3 - ProTeAN: Brain Organoids

4 - Microglia and Neurodevelopment

Ongoing Research Projects

• Modulation of a GPCRs regulatory proteins in synaptic physiology and autism

Autism spectrum disorder (ASD) is characterized by persistent deficits in social behaviors, communication, and the presence of restricted interests and stereotypies. When including milder forms, large-scale surveys have found that 1 in 54 children are diagnosed with this condition.

Several lines of evidence from ASD and intellectual disability animal models have shown there is common impairment in metabotropic glutamate receptor (mGluR) signaling. However, while these receptors are critical for neuronal plasticity, our knowledge of the cellular elements that directly interact and regulate surface expression of mGluRs is presently very limited.

Direct modulation of these receptors using pharmacological approaches, while very promising in rescuing the phenotype of animal models, has provided disappointing results in humans due to poor drug tolerability, and adverse side-effects. Presently, major limitations to tackle this problem and design novel therapies is twofold, (i) we lack a significant amount of information on the precise cell types that are more vulnerable to discrete ASD risk gene mutations and (ii) we currently do not have tools to regulate mGluRs in a cell-specific manner.

To tackle the gap in our understanding of mGluR regulation, we recently investigated the role of the family of G-protein coupled receptor-associated sorting proteins (GPRASPs). This large family of genes is known to regulate G-protein coupled receptors (GPCRs) such as mGluRs, by targeting internalized receptors towards lysosomal degradation.

• Early life stress, social hierarchies and the prefrontal cortex

Neurological illnesses, including those causing psychiatric and cognitive symptoms, affect over 50 million people worldwide and impose a tremendous burden on patients, families and society as a whole. Although genetics has been shown to contribute to these disorders, it only accounts for a small percentage of cases and fails to explain the interindividual variance observed in both emotional and cognitive outcomes. In this context, environmental factors have been proposed to underlie vulnerability to mental illness, particularly during sensitive periods of development. There is now strong epidemiological evidence correlating exposure to early life adversity (ELA), in the form of poverty, neglect or abuse, with aberrant brain maturation and a higher risk of developing a variety of psychiatric symptoms, cognitive deficits and memory problems later in life. Importantly, among the different forms of adversity, the emotional aspects related with the absence or unpredictability of nurturing signals, particularly when experienced in the first 2-3 years of life, seem to most profoundly influence and predict disease outcomes.

Our previous results have shown that a critical alteration in ELA mice, is a phenotype of social subordinance and alterations in the inhibitory system in the prefrontal cortex. Our current investigation is focusing on specific neuronal subtypes and their interplay with microglia cells as the early life stress is ongoing.

• Minibrains and neurodevelopmental disorders

This project aims to  create novel mechanistic insight into neurodevelopmental disorders and to identify novel therapeutic targets. Disorders such as autism spectrum disorder (ASD), intellectual disability, and attention-deficit/hyperactivity disorder, affect over 3% of children worldwide. Prevailing hypothesis has focused on defective synaptic pathways and neuronal circuits. However, sequencing studies pivoted the field into a novel direction as they revealed highly penetrant mutations in genes involved in chromatin remodeling and transcriptional regulation. It is now clear that, in addition to direct synaptic disruption, the genetic contribution to ASD acts through alterations in chromatin regulatory mechanisms in human brain development and function.

The goal of this project is to model neurodevelopmental disorders using dental stem cell-derived brain organoids from patients and controls to explore how mutations and environmental stimuli affect neuronal development and synaptogenesis-related proteins. Dental stem cell-derived brain organoids are providing us with unprecedented models that rely on minimally invasive sample collection. We believe this model has the potential to reduce and contain the costs (economic and ethical) associated with drug development and the usage of animal models.

• Environmental triggers shape microglia function in the cerebellum and prefrontal cortex

Microglia activation is a generic term often used to refer to any microglial response occurring following an insult. It is broadly characterized by clonal expansion, secretion of inflammatory cytokines and activation of clearing mechanisms, such as phagocytosis. Microglia activation has been described in most brain diseases, including neuropsychiatric conditions, such as autism, schizophrenia and attention-deficit/hyperactivity disorder. Although immune responses mediated by these cells have been substantially described in pathological scenarios, recent studies have demonstrated that some characteristics of activation-like processes may be physiologically relevant for microglia’s role during brain development.

We are interested in understanding how environmental triggers, such as early-life adversities and allergies, which are risk factors for the development of neuropsychiatric conditions, may impact the function of microglia during the maturation of neuronal circuits, specifically in what concerns myelination and pruning of neurons and synapses. We hypothesize that alterations in physiological microglial phenotypes in critical periods of circuit maturation may impair neuronal function in adulthood and underlie behavioral deficits reminiscent of neurodevelopmental disorders.

We are particularly interested in the cerebellum and prefrontal cortex, since these brain regions are affected in these diseases and suffer important circuit maturation processes after birth.


Publicizing Sheet

 

External Collaborations 

• Gouping Feng - https://fenglaboratory.org/guoping-feng/
• Frauke Zipp - https://www.unimedizin-mainz.de/neurologie/forschung/arbeitsgruppen/neuroimmunologie.html
• Jorge Almeida - http://proactionlab.fpce.uc.pt/
• Patricia Monteiro - http://www.icvs.uminho.pt/about-icvs/people/patriciamonteiro

Funding Agencies

• Portuguese Foundation for Science and Technology (FCT)
• European Commision - Marie Curie Actions
• Bial Foundation
• Gulbenkian Foundation
• Brain & Behavior Research Foundation

Selected Publications

• Li Y, Lopez-Huerta VG, Adiconis X, Levandowski K, Choi S, Simmons SK, Arias-Garcia MA, Guo B, Yao AY, Blosser TR, Wimmer RD, Aida T, Atamian A, Naik T, Sun X, Bi D, Malhotra D, Hession CC, Shema R, Gomes M, Li T, Hwang E, Krol A, Kowalczyk M, Peça J, Pan G, Halassa MM, Levin JZ, Fu Z, Feng G. (2020) Distinct subnetworks of the thalamic reticular nucleus. Nature Jul 22. https://doi.org/10.1038/s41586-020-2504-5
• Franco, L. O., Carvalho, M. J., Costa, J., Ferreira, P. A., Guedes, J. R., Sousa, R., Edfawy, M., Seabra, C. M., Cardoso, A. L., & Peça, J. (2020). Social subordination induced by early life adversity rewires inhibitory control of the prefrontal cortex via enhanced Npy1r signaling. Neuropsychopharmacology, 10.1038/s41386-020-0727-7. https://doi.org/10.1038/s41386-020-0727-7
• Barros-Viegas, A. T., Carmona, V., Ferreiro, E., Guedes, J., Cardoso, A. M., Cunha, P., Pereira de Almeida, L., Resende de Oliveira, C., Pedro de Magalhães, J., Peça, J., & Cardoso, A. L. (2020). miRNA-31 Improves Cognition and Abolishes Amyloid-β Pathology by Targeting APP and BACE1 in an Animal Model of Alzheimer’s Disease. Molecular therapy. Nucleic acids, 19, 1219–1236. https://doi.org/10.1016/j.omtn.2020.01.010
• Luís F. Ribeiro, Tatiana Catarino, Mário Carvalho, Sandra D. Santos, Luísa Cortes, Patricio O. Opazo, Lyn Rosenbrier Ribeiro, Daniel Choquet, José A. Esteban, João Peça, Ana Luísa Carvalho (2020) Constitutive ghrelin receptor activity modulates AMPA receptor traffic and supports memory formation. bioRxiv 2020.02.05.934463; doi: https://doi.org/10.1101/2020.02.05.934463
• Edfawy, M., Guedes, J. R., Pereira, M. I., Laranjo, M., Carvalho, M. J., Gao, X., Ferreira, P. A., Caldeira, G., Franco, L. O., Wang, D., Cardoso, A. L., Feng, G., Carvalho, A. L., & Peça, J. (2019). Abnormal mGluR-mediated synaptic plasticity and autism-like behaviours in Gprasp2 mutant mice. Nature communications, 10(1), 1431. https://doi.org/10.1038/s41467-019-09382-9
• Lima Caldeira, G., Peça, J., & Carvalho, A. L. (2019). New insights on synaptic dysfunction in neuropsychiatric disorders. Current opinion in neurobiology, 57, 62–70. https://doi.org/10.1016/j.conb.2019.01.004
• Sequeira DB, Seabra CM, Palma PJ, Cardoso AL, Peça J, Santos JM. Effects of a New Bioceramic Material on Human Apical Papilla Cells. J Funct Biomater. (2018);9(4):74. Published 2018 Dec 16. https://doi.org/10.3390/jfb9040074
• Peça, J., Feliciano, C., Ting, J. T., Wang, W., Wells, M. F., Venkatraman, T. N., Lascola, C. D., Fu, Z., & Feng, G. (2011). Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature, 472(7344), 437–442. https://doi.org/10.1038/nature09965
• Welch, J. M., Lu, J., Rodriguiz, R. M., Trotta, N. C., Peca, J., Ding, J. D., Feliciano, C., Chen, M., Adams, J. P., Luo, J., Dudek, S. M., Weinberg, R. J., Calakos, N., Wetsel, W. C., & Feng, G. (2007). Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature, 448(7156), 894–900. https://doi.org/10.1038/nature06104
• *Wang, H., *Peca, J., *Matsuzaki, M., Matsuzaki, K., Noguchi, J., Qiu, L., Wang, D., Zhang, F., Boyden, E., Deisseroth, K., Kasai, H., Hall, W. C., Feng, G., & Augustine, G. J. (2007). High-speed mapping of synaptic connectivity using photostimulation in Channelrhodopsin-2 transgenic mice. PNAS, 104(19), 8143–8148. https://doi.org/10.1073/pnas.0700384104