MedicalResearch.com Interview with:
Prof. Carmen Sandi
Director, Brain Mind Institute
Laboratory of Behavioral Genetics
Brain Mind Institute
Ecole Polytechnique Federale de Lausanne
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: We are interested in understanding how the brain regulates social behaviors and aggression, both in healthy individuals and individuals with psychiatric disorders. In our recent publication in Molecular Psychiatry, we investigated the impact of an alteration in a gene, St8sia2, that plays important roles during early brain development. Alterations in this gene have been linked with schizophrenia, autism and bipolar disorder, and individuals with these disorders frequently present high aggressiveness. In addition, expression of this gene in the brain can be altered by stressful insults during very early life and development.
Our study shows that genetic and environmental conditions linked to a reduction in the expression of this neuroplasticity gene during early life can lead to impaired fear learning and associated pathological aggression. We could further reveal that deficits in St8sia2 expression lead to a dysfunction in a receptor in the amygdala (a brain region critically involved in emotionality and fear learning), the GluN2B subunit of NMDA Receptors.
This allowed us to target this receptor with D-cycloserine, a drug that facilitates NMDA receptor function. This treatment, when given acutely, ameliorated the capacity to learn from adversity and reduced individuals’ aggressiveness.
MedicalResearch.com: What should readers take away from your report?
Response: Our study has allowed to identify alterations in brain mechanisms that control fear learning, a process which is very relevant in the socialization of children. Incapacity to learn from fear or punishment makes education difficult. Our work identifies a key mechanism in this process that is disrupted by genetic and early traumatic conditions that lead to aggression. This allows testing drugs and other treatments that can tackle this process as potential ways to ameliorate aggressive dysfunctions.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: It would be important to start testing if individuals with callous-unemotional or psychopathic traits would benefit by the drug that we identify as beneficial in our study. In case of positive results, it would then be important to test the treatment in individuals with psychiatric disorders presenting high levels of aggression.
MedicalResearch.com: Is there anything else you would like to add?
Response: It is important to indicate that research in the field of aggression has been very reduced in the past. Only very recently, research agencies and foundations have started supporting research in this topic. That means that the state of knowledge in this field is still very incipient. The current view is that aggression can, indeed, have genetic and environmental (particularly early life insults and traumas) causes, and that genetic susceptibility enhances vulnerability to environmental influences. Early life stress, including traumatic experiences, neglect and maltreatment are certainly strong factors that increase the susceptibility of individuals to develop as highly aggressive. In addition, some genetic risk factors and mutations can also affect brain development and shape individuals with high aggressive traits. Our study advances on the understanding of altered brain mechanisms leading to aggression, of both genetic and environmental nature.
Alexandre Bacq, Simone Astori, Elias Gebara, Wei Tang, Bianca A. Silva, Jose Sanchez-Mut, Jocelyn Grosse, Isabelle Guillot de Suduiraut, Olivia Zanoletti, Catherine Maclachlan, Graham W. Knott, Johannes Gräff, Carmen Sandi. Amygdala GluN2B-NMDAR dysfunction is critical in abnormal aggression of neurodevelopmental origin induced by St8sia2 deficiency. Molecular Psychiatry, 2018; DOI: 10.1038/s41380-018-0132-3
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