TY - JOUR
T1 - Interneuron activity controls endocannabinoid-mediated presynaptic plasticity through calcineurin
AU - Heifets, Boris D.
AU - Chevaleyre, Vivien
AU - Castillo, Pablo E.
PY - 2008/7/22
Y1 - 2008/7/22
N2 - 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 Ca2+ dynamics all blocked I-LTD, strongly suggesting that IN spikes regulate I-LTD by raising Ca2+ at the nerve terminal. Finally, inhibiting the Ca2+-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.
AB - 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 Ca2+ dynamics all blocked I-LTD, strongly suggesting that IN spikes regulate I-LTD by raising Ca2+ at the nerve terminal. Finally, inhibiting the Ca2+-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.
KW - CA1
KW - CB1
KW - Hippocampus
KW - Inhibition
KW - LTD
UR - http://www.scopus.com/inward/record.url?scp=48249090807&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=48249090807&partnerID=8YFLogxK
U2 - 10.1073/pnas.0711880105
DO - 10.1073/pnas.0711880105
M3 - Article
C2 - 18632563
AN - SCOPUS:48249090807
SN - 0027-8424
VL - 105
SP - 10250
EP - 10255
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 29
ER -