Modulation of Astroglial Glutamate Transporters by CB1 Receptor Shapes Endocannabinoid-Mediated Long-Term Depression in the Medial Prefrontal Cortex

Abstract

Abstract Excitatory Amino Acid Transporters (EAATs), prominently expressed in astrocytes, are dynamic proteins crucial for synaptic function and plasticity, notably in long-term depression (LTD). However, the precise adaptations in glutamate uptake during LTD remain elusive. Within the medial prefrontal cortex (mPFC), endocannabinoid (eCB) signaling assumes a central role in synaptic plasticity, ultimately affecting memory and mood regulation. In astrocytes, CB1R activation increases intracellular Ca2+. We therefore hypothesize that astroglial CB1R could shape eCBD-LTD through EAATs modulation. By performing ex vivo Ca2+ imaging and electrophysiological recordings we could conclude that LTD in mPFC is astroglial Ca2+-dependent, through a mechanism that involves a CB1R-mediated inhibition of glutamate transport activity. Importantly also, we were able to rescue LTD under deficient Ca2+ levels in astrocytes. Our findings provide evidence that CB1R-mediated decrease of EAATs activity through astroglial Ca2+-dependent mechanism is crucial for LTD maintenance.