Interneuron activity controls endocannabinoid-mediated presynaptic plasticity through calcineurin

Boris D. Heifets, Vivien Chevaleyre, Pablo E. Castillo

Research output: Contribution to journalArticle

80 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)10250-10255
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number29
DOIs
StatePublished - Jul 22 2008

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Keywords

  • CA1
  • CB1
  • Hippocampus
  • Inhibition
  • LTD

ASJC Scopus subject areas

  • General

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