The role of carbonic anhydrases in extinction of contextual fear memory

• Published in: Proceedings of the National Academy of Sciences - PNAS 2020-07, Vol.117 (27), p.16000-16008
• Main Authors: Schmidt, Scheila Daiane, Costa, Alessia, Rani, Barbara, Nachtigall, Eduarda Godfried, Passani, Maria Beatrice, Carta, Fabrizio, Nocentini, Alessio, de Carvalho Myskiw, Jociane, Furini, Cristiane Regina Guerino, Supuran, Claudiu T., Izquierdo, Ivan, Blandina, Patrizio, Provensi, Gustavo
• Format: Article
• Language: English
• Subjects: Acetazolamide; Amygdala; Animals; Basolateral Nuclear Complex - physiology; Bicarbonates; Biological Sciences; Brain; c-Fos protein; CA1 Region, Hippocampal - physiology; Carbon dioxide; Carbonic anhydrases; Carbonic Anhydrases - metabolism; Catalytic activity; Consolidation; Emotions; Fear; Fear - physiology; Fear conditioning; Hippocampus; Isoforms; Learning; Male; Memory - physiology; Mice; Phenylalanine; Prefrontal cortex; Prefrontal Cortex - physiology; Proto-Oncogene Proteins c-fos - metabolism; Protons; Rats; Rats, Wistar; Substantia nigra
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1910690117

Carbonic anhydrases (CAs; EC 4.2.1.1) are metalloenzymes present in mammals with 16 isoforms that differ in terms of catalytic activity as well as cellular and tissue distribution. CAs catalyze the conversion of CO₂ to bicarbonate and protons and are involved in various physiological processes, including learning and memory. Here we report that the integrity of CA activity in the brain is necessary for the consolidation of fear extinction memory. We found that systemic administration of acetazolamide, a CA inhibitor, immediately after the extinction session dose-dependently impaired the consolidation of fear extinction memory of rats trained in contextual fear conditioning. D-phenylalanine, a CA activator, displayed an opposite action, whereas C18, a membraneimpermeable CA inhibitor that is unable to reach the brain tissue, had no effect. Simultaneous administration of acetazolamide fully prevented the procognitive effects of D-phenylalanine. Whereas Dphenylalanine potentiated extinction, acetazolamide impaired extinction also when infused locally into the ventromedial prefrontal cortex, basolateral amygdala, or hippocampal CA1 region. No effects were observed when acetazolamide or D-phenylalanine was infused locally into the substantia nigra pars compacta. Moreover, systemic administration of acetazolamide immediately after the extinction training session modulated c-Fos expression on a retention test in the ventromedial prefrontal cortex of rats trained in contextual fear conditioning. These findings reveal that the engagement of CAs in some brain regions is essential for providing the brain with the resilience necessary to ensure the consolidation of extinction of emotionally salient events.