Abstract
The amygdala plays a crucial role in attaching emotional significance to environmental cues. Its intercalated cell masses (ITC) are tight clusters of GABAergic neurons, which are distributed around the basolateral amygdala complex. Distinct ITC clusters are involved in the acquisition and extinction of conditioned fear responses. Previously, we have shown that fear memory retrieval reduces the AMPA/NMDA ratio at thalamic afferents to ITC neurons within the dorsal medio-paracapsular cluster. Here, we investigate the molecular mechanisms underlying the fear-mediated reduction in the AMPA/NMDA ratio at these synapses and, in particular, whether specific changes in the synaptic density of AMPA receptors underlie the observed change. To this aim, we used a detergent-digested freeze-fracture replica immunolabeling technique (FRIL) approach that enables to visualize the spatial distribution of intrasynaptic AMPA receptors at high resolution. AMPA receptors were detected using an antibody raised against an epitope common to all AMPA subunits. To visualize thalamic inputs, we virally transduced the posterior thalamic complex with Channelrhodopsin 2-YFP, which is anterogradely transported along axons. Using face-matched replica, we confirmed that the postsynaptic elements were ITC neurons due to their prominent expression of μ-opioid receptors. With this approach, we show that, following auditory fear conditioning in mice, the formation and retrieval of fear memory is linked to a significant reduction in the density of AMPA receptors, particularly at spine synapses formed by inputs of the posterior intralaminar thalamic and medial geniculate nuclei onto identified ITC neurons. Our study is one of the few that has directly linked the regulation of AMPA receptor trafficking to memory processes in identified neuronal networks, by showing that fear-memory induced reduction in AMPA/NMDA ratio at thalamic-ITC synapses is associated with a reduced postsynaptic AMPA receptor density.
Highlights
We show here that following auditory fear conditioning in mice, the formation and retrieval of fear memory is linked to a significant reduction in the density of amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in synapses made by posterior intralaminar nuclei of the thalamus (PIN)/medial subdivision of the medial geniculate nucleus (MGm) inputs onto identified dorsal medio-paracapsular cluster (mpITC) neurons
Our findings suggest that the decrease in A/N ratio observed at the same synapses upon fear memory retrieval (Asede et al, 2015) results from an altered trafficking of AMPA receptors, and in particular their removal from the postsynaptic membrane specialization (PSD) of spine synapses
We have previously reported that fear memory retrieval is associated with an increase in paired pulse ratio (PPR) of the AMPA-EPSC at PIN/MGm-mpITC synapses (Asede et al, 2015)
Summary
Associative learning is an adaptive process that allows an individual to predict events and requires long-lasting modifications in the strength of synaptic connections, generally known as synaptic plasticity (Martin et al, 2000; Malenka and Bear, 2004; Kessels and Malinow, 2009; Poo et al, 2016).Pavlovian fear (threat) conditioning is one of the most prominently studied forms of associative learning (LeDoux, 2000; Maren, 2001), in which a neutral sensory stimulus (conditioned stimulus or CS) is repeatedly paired with an aversive stimulus (unconditioned stimulus or US; most commonly an electric shock), which leads to the formation of a strong CS-US association. LA neurons transfer the association via the basal and basomedial nuclei to the medial division of the central nucleus (CeA) to generate fear outputs (Maren and Quirk, 2004) This simple model has been recently challenged since other amygdaloid structures besides the LA, e.g., the lateral part of the CeA (CeL) and the intercalated cell masses of the amygdala (ITCs), were shown to receive direct sensory information and undergo fear-related synaptic and cellular plasticity (Ciocchi et al, 2010; Haubensak et al, 2010; Li et al, 2013; Herry and Johansen, 2014; Asede et al, 2015; Barsy et al, 2020)
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