Endocannabinoid Signaling Mediates Local Dendritic Coordination between Excitatory and Inhibitory Synapses

Abstract

Highlights d Two-photon glutamate uncaging is used to stimulate clustered excitatory spines d Spine stimulation can trigger inhibitory bouton growth onto the same dendrite d The dendrite triggers presynaptic inhibitory changes via endocannabinoid signaling d This mechanism may ensure local inhibitory control of active excitatory clusters

CB1-receptor-mediated inhibitory LTD triggers presynaptic remodeling via protein synthesis and ubiquitination

“…Here, we provide evidence for long-term structural changes at mature CB 1 + terminals associated with CB 1 -iLTD. Previous work showed CB 1 receptor activation can trigger ultrastructural changes in vesicle distribution associated with short-term CB 1 -mediated plasticity ( García-Morales et al, 2015 ; Ramírez-Franco et al, 2014 ), collapse of axonal growth cones ( Berghuis et al, 2007 ), and inhibitory bouton formation in response to strong postsynaptic excitation ( Hu et al, 2019 ). Our data show that transient activation of CB 1 receptors leads to a long-term reduction of the presynaptic CB 1 + compartment volume in somatic synapses onto CA1 pyramidal cells.…”

Lights on Endocannabinoid-Mediated Synaptic Potentiation

“…long-lasting neural changes induced by activity at a given time, and that modulate subsequently induced plasticity (Abraham, 2008 ), orchestrated by eCBs. This i-LTD is finely tuned by the parallel activation of CB 1 R on GABAergic or glutamatergic cells (Monory et al, 2015 ) and is also accompanied by changes in excitability enhancing the spiking probability in response to a given EPSP, i.e ., EPSP-to-spike potentiation (Chevaleyre and Castillo, 2003 ; Orr et al, 2014 ; Kim et al, 2019 ), and by structural changes (Monory et al, 2015 ; Hu et al, 2019 ) both eCB-mediated. Interestingly, a circuit-based synaptic learning rule, consisting of paired stimulation of the perforant path and Schaffer collaterals, induced an input-timing-dependent heterosynaptic LTP at CA3-CA1 but not at cortical-CA1 synapses (Xu et al, 2012 ; Basu et al, 2013 ).…”

“…Importantly, since eCBs can act as bimodal regulators of synaptic plasticity and interact with several neuromodulators, eCB-mediated LTP could also be switched back to normal, or turned to depression (Wang et al, 2014 ; Caballero-Florán et al, 2016 ; Xu et al, 2018 ), depending for instance on late behavioral outcomes, such as in reinforcement learning. During consolidation (III) eCB-mediated potentiation of inhibitory transmission and structural synaptic changes can stabilize acquired memory engrams (Monory et al, 2015 ; Ghosh et al, 2018 ; Hu et al, 2019 ). Finally, reactivation of memories (IV) especially emotional ones, increases eCB signaling, which can operate in feedback and control the lability of these memory traces by modifying the E/I balance (Li et al, 2008 ; Segev et al, 2018 ).…”

Exciting inhibition: Local regulation of synapse formation and plasticity

“…It would be interesting to use GABA uncaging to assess changes in the strength of individual inhibitory synapses. Coordination between excitation and inhibition, which is crucial for the proper functioning of neurons, is regulated at the synaptic level (Bloss et al, 2016;Hu et al, 2019;Liu, 2004). We therefore expect that improving our understanding of the interaction of excitatory and inhibitory plasticity at the level of single synapses and dendrites, for example by combining two-photon uncaging of glutamate and GABA , will provide us with exciting new insights.…”

“…This phase is then followed by a plateau (or sustained phase) where the spine growth declines and stabilizes, typically at 50-100% (Bosch et al, 2014;Patterson et al, 2010;. Other studies report a gradual spine growth over the course of 5-10 minutes, which then stabilizes at a plateau, without a significant peak Hayama et al, 2013;Hu et al, 2019;. Even when comparing studies that show a similar temporal pattern of spine growth, peak and plateau magnitudes often vary significantly.…”