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

Abstract

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 benzodiazepinesensitive (BZD) GABA A receptors containing the a2 subunit without altering the intrasynaptic distribution and overall amount of BZD-GABA A 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.

Deficiency of the CYLD Impairs Fear Memory of Mice and Disrupts Neuronal Activity and Synaptic Transmission in the Basolateral Amygdala

“…This result implies the possibility of a presynaptic change in the release of inhibitory neurotransmitters or the number of GABAergic interneurons. A large body of evidence suggested that the formation and expression of conditioned fear memories also entails long-lasting functional and structural plasticity of GABAergic synapses onto pyramidal neurons of the murine BLA (Kasugai et al, 2019). Available data support the contention that PV + interneurons play an important role in modulating the balance of excitation and inhibition in local circuits and they are thus involved in the regulation of fear memory (Hu et al, 2014;Lucas and Clem, 2018;Wang et al, 2020).…”

Anandamide Signaling Augmentation Rescues Amygdala Synaptic Function and Comorbid Emotional Alterations in a Model of Epilepsy

“…Conversely, we did find both iLTD induction and iLTD-mediated LTP modulation significantly impaired following repeated amygdala seizures, indicating that repeated seizure activity alters synaptic plasticity specifically at GABA synapses. Structural and functional plasticity of GABAergic synapses in the BA has been shown to occur during fear conditioning (Kasugai et al, 2019), thereby, it is possible to speculate that alterations of GABA plasticity induced by seizures likely account for the altered fear memory retention in kindled rats. However, previous studies indicate that a persistent reduction of basal GABAergic activity together with a sustained increase of the excitatory drive within the BLA is generally associated with increased fear expression (Ehrlich et al, 2009).…”

Hyperexcitability and Loss of Feedforward Inhibition Contribute to Aberrant Plasticity in theFmr1KO Amygdala

“…At the cellular level, the BLA is composed of excitatory principal neurons (PNs) and a diverse population of GABAergic inhibitory interneurons (INs; McDonald, 1984 ; Sah et al, 2003 ; Duvarci and Pare, 2014 ). These local PNs undergo input-specific, activity-dependent plastic changes in response to co-occurring threatening and sensory stimuli ( Quirk et al, 1995 ; McKernan and Shinnick-Gallagher, 1997 ; Schoenbaum et al, 1999 ; Nabavi et al, 2014 ; Grewe et al, 2017 ; Kim and Cho, 2017 ; Kasugai et al, 2019 ). Importantly, these co-occurring stimuli depolarize and drive ensembles of BLA PNs to fire action potentials (APs), and this excitation is necessary for learning to occur ( Rosenkranz and Grace, 2002 ; Wolff et al, 2014 ; Grewe et al, 2017 ).…”