Structural and Functional Remodeling of Amygdala GABAergic Synapses in Associative Fear Learning

• Published in: Neuron (Cambridge, Mass.) Mass.), 2019-11, Vol.104 (4), p.781-794.e4
• Main Authors: Kasugai, Yu, Vogel, Elisabeth, Hörtnagl, Heide, Schönherr, Sabine, Paradiso, Enrica, Hauschild, Markus, Göbel, Georg, Milenkovic, Ivan, Peterschmitt, Yvan, Tasan, Ramon, Sperk, Günther, Shigemoto, Ryuichi, Sieghart, Werner, Singewald, Nicolas, Lüthi, Andreas, Ferraguti, Francesco
• Format: Article
• Language: English
• Subjects: Amygdala; Animals; Association Learning - physiology; Associative learning; Benzodiazepines; Brain; Conditioning, Classical - physiology; extinction; Extinction behavior; Extinction, Psychological - physiology; Fear - physiology; Fear conditioning; freeze-fracture; Functional plasticity; GABA; GABAA receptors; GABAergic Neurons - physiology; gating kinetics; Glutamatergic transmission; Immunoglobulins; inhibition; learning; Life Sciences; Male; Mice, Inbred C57BL; Neural networks; Neuronal Plasticity - physiology; Neurons; Neurons and Cognition; plasticity; Pyramidal cells; Software; Structure-function relationships; synapse; Synapses; Synaptic plasticity; γ-Aminobutyric acid A receptors
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2019.08.013

Associative learning is thought to involve different forms of activity-dependent synaptic plasticity. Although previous studies have mostly focused on learning-related changes occurring at excitatory glutamatergic synapses, we found that associative learning, such as fear conditioning, also entails long-lasting functional and structural plasticity of GABAergic synapses onto pyramidal neurons of the murine basal amygdala. Fear conditioning-mediated structural remodeling of GABAergic synapses was associated with a change in mIPSC kinetics and an increase in the fraction of synaptic benzodiazepine-sensitive (BZD) GABAA receptors containing the α2 subunit without altering the intrasynaptic distribution and overall amount of BZD-GABAA receptors. These structural and functional synaptic changes were partly reversed by extinction training. These findings provide evidence that associative learning, such as Pavlovian fear conditioning and extinction, sculpts inhibitory synapses to regulate inhibition of active neuronal networks, a process that may tune amygdala circuit responses to threats. [Display omitted] •Fear learning induces structural and functional plasticity of GABAergic synapses•Fear learning increases the synaptic fraction of GABAA-Rs containing the α2 subunit•Plastic changes at GABAergic synapses are long lasting•Extinction partly reverses fear-mediated structural and functional plasticity Kasugai et al. show that associative learning, such as fear conditioning, elicits concerted structural and functional plasticity of amygdala GABAergic synapses. This process regulates both somatic and dendritic inhibition and may tune amygdala circuit responses to threats.