title: Interneuron activity controls endocannabinoid-mediated presynaptic plasticity through calcineurin.
abstract: Retrograde signaling by endocannabinoids (eCBs) mediates a widely expressed form of long-term depression at excitatory and inhibitory synapses (eCB-LTD), involving a reduction in neurotransmitter release. In the hippocampus, eCB-LTD occurs at interneuron (IN)-pyramidal cell (PC) synapses (I-LTD), and its induction requires a presynaptic reduction of cAMP/PKA signaling resulting from minutes of type 1 cannabinoid receptor (CB1R) activation. Although repetitive activity of glutamatergic synapses initiates the eCB mobilization required for I-LTD, it is unclear whether CB1R-containing GABAergic terminals are passive targets of eCBs or whether they actively contribute to induction. Here, we show that the minutes-long induction period for I-LTD may serve as a window to integrate associated spontaneous activity in the same IN receiving the retrograde eCB signal. Indeed, reducing spontaneous IN firing blocked I-LTD, which could be rescued with extra stimulation of inhibitory afferents. Moreover, cell pair recordings showed that a single IN expressed LTD onto a PC only if it was active during eCB signaling. Several methods of disrupting presynaptic Ca(2+) dynamics all blocked I-LTD, strongly suggesting that IN spikes regulate I-LTD by raising Ca(2+) at the nerve terminal. Finally, inhibiting the Ca(2+)-activated phosphatase, calcineurin, fully blocked I-LTD, but blocking another phosphatase did not. Our findings support a model where both CB1R signaling and IN activity shift the balance of kinase and phosphatase activity in the presynaptic terminal to induce I-LTD.
authors.affiliation: Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Boris D
authors.initials: BD
authors.lastname: Heifets
authors.forename: Vivien
authors.initials: V
authors.lastname: Chevaleyre
authors.forename: Pablo E
authors.initials: PE
authors.lastname: Castillo
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000502:physiology*; D065095:Calcineurin Inhibitors; D020013:Calcium Signaling; D063385:Cannabinoid Receptor Modulators / Q000502:physiology*; D004558:Electric Stimulation; D004594:Electrophysiology; D063388:Endocannabinoids; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D066298:In Vitro Techniques; D007395:Interneurons / Q000187:drug effects / Q000502:physiology*; D036881:Long-Term Synaptic Depression; D009473:Neuronal Plasticity / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D065095:Calcineurin Inhibitors; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D043884:Receptor, Cannabinoid, CB1; D013779:Tetrodotoxin; D019703:Calcineurin