Interneuron activity controls endocannabinoid-mediated presynaptic plasticity through calcineurin

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 (CBIR) activation. Although repetitive activity of glutamatergic synapses initiates the eCB mobilization required for I-LTD, it is unclear whether CBIRcontaining 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.sup.2+] dynamics all blocked I-LTD, strongly suggesting that IN spikes regulate I-LTD by raising [Ca.sup.2+] at the nerve terminal. Finally, inhibiting the [Ca.sup.2+]-activated phosphatase, calcineurin, fully blocked I-LTD, but blocking another phosphatase did not. Our findings support a model where both CBIR signaling and IN activity shift the balance of kinase and phosphatase activity in the presynaptic terminal to induce I-LTD. CA1 | CB1 | hippocampus | inhibition | LTD