Activity-dependent modulation of hippocampal synaptic plasticity via PirB and endocannabinoids.

The threshold for Hebbian synaptic plasticity in the CNS is modulated by prior synaptic activity. At adult CA3-CA1 synapses, endocannabinoids play a role in this process, but how activity engages and maintains this retrograde signaling system is not well understood. Here we show that conditional deletion of Paired Immunoglobulin-like receptor B (PirB) from pyramidal neurons in adult mouse hippocampus results in deficient LTD at CA3-CA1 synapses over a range of stimulation frequencies, accompanied by an increase in LTP. This finding can be fully explained by the disengagement of retrograde endocannabinoid signaling selectively at excitatory synapses. In the absence of PirB, the NMDAR-dependent regulation of endocannabinoid signaling is lost, while CB1R-dependent and group I mGluR-dependent regulation are intact. Moreover, mEPSC frequency in mutant CA1 pyramidal cells is elevated, consistent with a higher density of excitatory synapses and altered synapse pruning. Mice lacking PirB also perform better than WT in learning and memory tasks. These observations suggest that PirB is an integral part of an NMDA receptor-mediated synaptic mechanism that maintains bidirectional Hebbian plasticity and learning via activity-dependent endocannabinoid signaling.