Retrograde endocannabinoid signaling at inhibitory synapses in vivo

Abstract

Endocannabinoid (eCB)–mediated suppression of inhibitory synapses has been hypothesized, but this has not yet been demonstrated to occur in vivo because of the difficulty in tracking eCB dynamics and synaptic plasticity during behavior. In mice navigating a linear track, we observed location-specific eCB signaling in hippocampal CA1 place cells, and this was detected both in the postsynaptic membrane and the presynaptic inhibitory axons. All-optical in vivo investigation of synaptic responses revealed that postsynaptic depolarization was followed by a suppression of inhibitory synaptic potentials. Furthermore, interneuron-specific cannabinoid receptor deletion altered place cell tuning. Therefore, rapid, postsynaptic, activity-dependent eCB signaling modulates inhibitory synapses on a timescale of seconds during behavior.

Neuromodulation of inhibitory synaptic transmission in the basolateral amygdala during fear and anxiety

“…Experimentally, endocannabinoids, particularly 2-AG, can be mobilized by strong depolarization of the postsynaptic neurons in brain slices to suppress the release of glutamate or GABA, a phenomenon known as depolarization-induced suppression of excitation (DSE) or inhibition (DSI), respectively ( Wilson et al, 2001 ; Wilson and Nicoll, 2001 ; Castillo et al, 2012 ). It was recently shown in vivo that discharges of place cells in the hippocampal CA1 region also trigger 2-AG release, which suppresses CCK basket cell-mediated inhibition ( Dudok et al, 2024 ). Under physiological conditions, stress, including acute restraint for 30 min, reliably elevates the level of 2-AG in the BLA in rodents ( Patel et al, 2005 ; Hill and McEwen, 2009 ; Hill and Tasker, 2012 ).…”

“…Vesicular GABA release is strongly modulated by endocannabinoids in CCK basket cell terminals, but not in PV basket cell terminals, due to the high expression of CB1 receptors in CCK neurons, but not in PV neurons ( Katona et al, 2001 ; Wilson et al, 2001 ; Yoshida et al, 2011 ; Rovira-Esteban et al, 2019 ). By virtue of abundant and selective expression of CB1 receptors on their axon terminals, CCK basket cells provide another level of modulation via DSI and G protein-coupled receptor-mediated eCB mobilization to sculpt circuit activity ( Di et al, 2016 ; Dudok et al, 2024 ). At the circuit level, the PV basket cells in the BLA receive much denser glutamatergic input than the CCK basket cells, resulting in a more reliable activation by synaptic stimulation of the PV basket cells than of the CCK basket cells ( Andrási et al, 2017 ).…”