OBJECTIVES

Brain function depends on a balance between excitatory and inhibitory neurotransmission. Alterations in the function of GABA_A receptors, which mediate the main inhibitory transmission in the central nervous system, are relevant for different neuropsychiatric disorders such as schizophrenia, anxiety, epilepsy and autism. The importance of GABA_A receptors in normal brain function, in pathological conditions and as targets of clinically relevant drugs has attracted interest to the regulatory mechanisms that control the activity of these receptors.

The research group studies the regulation of the GABAergic neurotransmission under physiological, pathological and pharmacological conditions in which a prolonged activation of the GABA_A receptors occurs.

MEMBERS

MARÍA CLARA GRAVIELLE

L CAROLINA GONZALEZ GOMEZ

RESEARCH LINES

USE-DEPENDENT REGULATION OF GABA-A RECEPTOR: MOLECULAR BASES OF TOLERANCE

The prolonged activation of GABA_Areceptors induces adaptive changes in the function of the receptors, which constitutes an example of neuronal plasticity. Chronic exposure to different exogenous drugs that potentiate GABA responses, such as benzodiazepines, barbiturates, and ethanol, induces tolerance by a process considered to be homeostatic. Benzodiazepines have been used in the clinic for over 50 years due to their high therapeutic index and low toxicity. However, their long-term use is limited by the development of tolerance to most of their pharmacological actions and by dependence. Because most pharmacological effects of benzodiazepines are mediated through binding to the GABA_A receptor, the mechanism of tolerance may involve compensating changes in the number, structure, and/or function of this receptor.We have studied the effect of the chronic diazepam administration, a classic benzodiazepine, on the development of tolerance in rats by means of behavioral and biochemical experiments. Tolerance was accompanied by a decreased in the interaction between GABA and benzodiazepine binding sites in the cerebral cortex, named uncoupling, which was estimated as a decrease in the potentiation of benzodiazepine binding by GABA. The development of tolerance was also associated with an alteration in the mRNA and protein levels of GABA_A receptor α1 subunit in the cerebral cortex that leads to a change in the subunit composition of the receptor. The aim of this project is to investigate the molecular bases of tolerance by elucidating the intracellular signaling cascade activated by the continuous exposure to benzodiazepines that results in the alterations of GABA_A receptors. From a therapeutic point of view, the understanding of the mechanism of benzodiazepine tolerance is critical to the design of drugs that could maintain their efficacy during long-term treatments.

RECENT PUBLICATIONS

-“PLASTICITY OF INHIBITORY CELLS IN HEALTH AND DISEASE” M. C. Gravielle, L. Pignataro, F. Varodayan. Front in Synaptic Neurosci, Editorial, 2023, 14: 1127609

 -“DIAZEPAM-INDUCED DOWN-REGULATION OF THE GABA_A RECEPTOR α1 SUBUNIT, AS MEDIATED BY THE ACTIVATION OF L-TYPE VOLTAGE-GATED CALCIUM CHANNEL/Ca²⁺/PROTEIN KINASE A SIGNALING CASCADE”. L. C. González Gómez, N. B. Medina, S. Sanz Blasco y M. C. Gravielle. Neurosci Lett, 2023, 810: 137358

-"REGULATION OF GABAA RECEPTORS INDUCED BY ACTIVATION OF L-TYPE VOLTAGE-GATED CALCIUM CHANNELS” M. C. Gravielle. Membranes, 11: 486, 2021

-"BENZODIAZEPINE EXPOSURE INDUCES TRANSCRIPTIONAL DOWN-REGULATION OF GABAA RECEPTOR α1 SUBUNIT GENE VIA L-TYPE VOLTAGE-GATED CALCIUM CHANNEL ACTIVATION IN RAT CEREBROCORTICAL NEURONS” M. F. Foitzick, N. B. Medina, L. C. Iglesias García y M. C. Gravielle Neurosci Lett, 721: 134801, 2020

-“REGULATION OF GABA_A RECEPTORS BY PROLONGED EXPOSURE TO ENDOGENOUS AND EXOGENOUS LIGANDS” C. Gravielle. Neurochem. Int., 118: 96, 2018

-“ACTIVATION-INDUCED REGULATION OF GABAA RECEPTORS: IS THERE A LINK WITH THE MOLECULAR BASIS OF BENZODIAZEPINE TOLERANCE?” C. Gravielle. Pharmacol. Res., 109: 92, 2016

-“EFFECT OF CHRONIC BENZODIAZEPINE EXPOSURE ON GABA-A RECEPTORS: REGULATION OF GABA/BENZODIAZEPINE SITE INTERACTIONS” C. Gravielle. In: “The Neuropathology of Drug Addictions and Substance Misuse” ed.by V. R. Preedy. Editorial: Academic Press., 2016.

-“TOLERANCE TO THE SEDATIVE AND ANXIOLYTIC EFFECTS OF DIAZEPAM IS ASSOCIATED WITH DIFFERENT ALTERATIONS OF GABA_A RECEPTORS IN RAT CEREBRAL CORTEX” C. Ferreri, M. L. Gutiérrez and M. C. Gravielle. Neuroscience, 310: 152, 2015.

-“WORKING MEMORY TRAINING TRIGGERS DELAYED CHROMATIN REMODELING IN THE MOUSE CORTICOSTRIATOTHALAMIC CIRCUIT” M. Cassanelli, M. L. Cladouchos, G. Fernández Macedo, L. Sifonios, L. Giaccardi, M. L. Gutiérrez, M. C. Gravielle and S. Wikinski. Prog.Neuropsychopharmacol. Biol. Psych., 60: 93, 2015.

-“GABA-INDUCED UNCOUPLING OF GABA/BENZODIAZEPINE SITE INTERACTIONS IS ASSOCIATED WITH INCREASED PHOSPHORYLATION OF THE GABA_A RECEPTOR” L. Gutiérrez, M. C. Ferreri, D. H. Farb and M. C. Gravielle. Neurosci. Res., 92: 1054, 2014.

-“GABA-INDUCED UNCOUPLING OF GABA/BENZODIAZEPINE SITE INTERACTIONS IS MEDIATED BY INCREASED OF GABA_A RECEPTOR INTERNALIZATION AND ASSOCIATED WITH A CHANGE IN SUBUNIT COMPOSITION” L. Gutiérrez, M. C. Ferreri and M. C. Gravielle. Neuroscience, 257: 119, 2014.

-“GENETIC DISRUPTION OF THE AUTISM SPECTRUM DISORDER RISK GENE PLAUR INDUCES GABA_A RECEPTOR SUBUNIT CHANGES” L. Eagleson, M. C. Gravielle, L. J. Schlueter McFadyen-Ketchum, S. J. Russek, D. H. Farb and P. Levitt. Neuroscience,168: 797, 2010.

-“PHARMACOLOGICAL PROPERTIES OF DOV315090, AN OCINAPLON METABOLITE” *D. Berezhnoy, *M. C. Gravielle, A. S. Basile, P. Skolnick and D. H. Farb. * Co-first authors. BioMed Central Pharmacology, 8: 11, 2008.

-“SURFACE EXPRESSION OF GABA(A) RECEPTORS IS TRANSCRIPTIONALLY CONTROLLED BY THE INTERPLAY OF CREB AND ITS BINDING PARTNER ICER” Hu, I. V. Lund, M. C. Gravielle, D. H. Farb, A. R. Brooks-Kayaland S. J. Russek. Biol. Chem., 283: 9328, 2008.

-“PHARMACOLOGY OF THE GABA_A RECEPTOR” Berezhnov, M. C. Gravielle and D. H. Farb. In: “The Handbook of Contemporary Neuropharmacology”, ed. by D. Sibley, I. Hanim, M. Kuhar, P. Skolnick. Editorial: J. Wiley & Sons, Inc., 2007.

-“MECHANISMS OF GABA_A AND GABA_B RECEPTOR GENE EXPRESSION” H. Farb, J. L. Steiger, S. C. Martin, M. C. Gravielle, T. T. Gibbs and S. J. Russek. In: “The GABA Receptor”, 3rd edition, ed. by S. Enna, H. Mohler and D. Odom. Editorial: The Humana Press, Inc., 2007.

FUNDING

-CONICET (PEI 68/97)

Role: Principal Investigator

 -CONICET (PIP 2005)

Role: Principal Investigator

-Universidad de Buenos Aires (UBACyTM073)

Role: Researcher

-Fundación Florencio Fiorini-Academia Nacional de Medicina (Subsidio para Investigaciones Biomédicas 2008)

Role: Principal Investigator

-Agencia Nacional de Promoción Científica y Tecnológica (PICT-2007-01059)

Role: Principal Investigator

-CONICET (PIP 2011)

Role: Principal Investigator

-CONICET (PIP 2014)

Role: Researcher

COLLABORATIONS

David H. Farb, Laboratory of Molecular Neurobiology, Department of Pharmacology and Experimental Therapeutics, School of Medicine, Universityof Boston, USA.