Evaluation of the effects of benzodiazepines on the in vivo electrophysiological activity of the brain and in vitro neuronal viability in the Ts65Dn mouse model

• Grant number: 16/17746-3
• Support type: Scholarships in Brazil - Doctorate
• Effective date (Start): May 01, 2017
• Effective date (End): December 31, 2021
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Carla Alessandra Scorza Bahi
• Grantee: Daniella Balduino Victorino
• Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated scholarship(s): 18/10131-9 - Effects of positive allosteric modulation on electrophysiological properties of GABAAR signaling in Ts65Dn mice and induced pluripotent stem cell-derived neurons from persons with Down syndrome, BE.EP.DR

Abstract

Down syndrome (DS) is the most common cause of intellectual disability of genetic etiology, affecting approximately 1 in 700 live births. Few advances have been made toward the elucidation of some of the mechanisms underlying the pathophysiology associated with DS, including the role of the gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mature central nervous system. As part of the wide range of phenotypes and comorbidities associated with, an increased incidence of epilepsy in individuals with DS in relation to the general population has been observed. Benzodiazepines (BZDs), which are positive allosteric modulators of the GABAA receptor, are widely used as first line drugs for the acute treatment of epilepsy. However, several studies have reported that BZDs are capable of induce paradoxical effects by increasing the neuronal excitation typically observed in seizure disorders. A recent study involving the Ts65Dn mouse, an animal model of DS, demonstrated that the intracellular concentration of chloride and the expression levels of the NKCC1 cotransporter were increased in the trisomic mice hippocampus. The consequence of such events was a shift in the GABA signaling from inhibitory to excitatory. Therefore, the aim of the present study is to evaluate the effects of BZDs on the in vivo electroencephalographic activity and in vitro neuronal viability in the Ts65Dn mouse. The successful execution of this study will provide a better understanding of the mechanisms involved in the neurobiology of the modulation of the intracellular concentration of chloride and in the emergence of GABA-mediated excitatory neurotransmission in DS. Furthermore, the experimental results of this project may aid the development of better therapeutic strategies to treat epilepsy in persons with DS, as well as contribute to the elucidation of the molecular mechanisms underlying the phenotypic consequences of the trisomy 21. Finally, this work should also provide valuable data for the potential identification of new pharmacological approaches aiming at enhancing the cognitive abilities of individuals with DS. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

VICTORINO, DANIELLA B.; SCOTT-MCKEAN, JONAH J.; JOHNSON, MARK W.; COSTA, ALBERTO C. S. Quantitative Analysis of Retinal Structure and Function in Two Chromosomally Altered Mouse Models of Down Syndrome. INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, v. 61, n. 5 MAY 2020. Web of Science Citations: 0.

GUIMARAES MARQUES, MARCIA JONATHAS; REAL, CAROLINE CRISTIANO; VICTORINO, DANIELLA BALDUINO; BRITTO, LUIZ ROBERTO; CAVALHEIRO, ESPER ABRAO; SCORZA, FULVIO ALEXANDRE; FERRAZ, HENRIQUE BALLALAI; SCORZA, CARLA ALESSANDRA. Endogenous protection against the 6-OHDA model of Parkinson's disease in the Amazonian rodent Proechimys. Neuroscience Letters, v. 709, SEP 14 2019. Web of Science Citations: 1.