Endocannabinoids and the persistent loss of inhibition at central synapses
Heifets, Boris Dov
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Changes in synaptic strength are widely believed to underlie processes like learning and memory. Although the best known mechanisms of synaptic plasticity involve regulation of postsynaptic receptors, increasing evidence also implicates long lasting changes in neurotransmitter release in complex cognitive processes. Retrograde signaling by endocannabinoids (eCBs) mediates both short and long-term depression (eCB-STD and eCB-LTD) of excitatory and inhibitory synaptic transmission, making it among the most widespread forms of synaptic plasticity in the brain. Both eCB-STD and eCB-LTD require the activation of the Type 1 Cannabinoid (CB1) receptor, a G protein-coupled receptor localized at presynaptic terminals which eCBs act to inhibit neurotransmitter release. Interneuron-to-pyramidal cell synapses in hippocampal area CA1 show both types of plasticity: a short term form is known as Depolarization-induced Supression of Inhibition (DSI), and a long term form, Long Term Depression of Inhibition (I-LTD). While DSI is presumably due to inhibition of presynaptic voltage-gated calcium channels (VGCC) by the G protein beta/gamma subunits, the mechanisms downstream of CB1 receptors underlying I-LTD are unknown. Furthermore, it is unknown whether I-LTD is a passive process, induced by eCBs alone, or whether interneuron activity contributes to plasticity in this critical brain region. We examined these issues in both the rodent hippocampus (area CA1) and amygdala, monitoring inhibitory synaptic transmission in these structures using acutely dissected brain slices prepared from juvenile rats and mice.;In hippocampus, we found that CB1 receptors trigger I-LTD through their action on a major signaling pathway, cAMP and the cAMP dependent protein kinase (PKA), implicated in other forms of long term plasticity. We also found that through this pathway, I-LTD induction targets the transmitter release machinery, in particular the active zone protein RIM1alpha. Notably, neither cAMP/PKA signaling, nor RIM1alpha were required for DSI. Importantly, similar findings were observed in the amygdala where we found that CB1 receptors act through cAMP/PKA signaling, and RIM1alpha is required for eCB-mediated I-LTD. Taken together our results show that in addition to the transient blockade of presynaptic VDCC, CB1 receptors can target the release machinery via PKA to trigger long-term depression of GABA release. This mechanism is found in both hippocampus and the amygdala, and may represent a general mechanism underlying eCB-LTD and presynaptic plasticity in other brain structures.;We next investigated whether eCBs are sufficient to induce I-LTD, or if perhaps I-LTD is an associative form of plasticity, requiring both eCBs and another temporally coincident signal, such as interneuron firing. We found that globally reducing spontaneous interneuron firing blocked I-LTD, but stimulating inhibitory afferents for a few minutes could rescue this deficit. Similarly, transient application of a CB1 receptor agonist triggered a long lasting depression of field IPSPs only if either spontaneous interneuron activity was intact, or inhibitory afferents were stimulated. Using cell-pair recordings, we found that a single interneuron expressed LTD onto a pyramidal cell only if the interneuron was active during eCB signaling. We hypothesized that interneuron spikes control presynaptic CB1 receptor signaling by raising calcium at the nerve terminal. In fact, transiently removing extracellular calcium, buffering presynaptic calcium or blocking presynaptic calcium stores all blocked I-LTD. Finally, inhibiting the calcium activated phosphatase 2B, calcineurin, fully blocked I-LTD, but a phosphatase 1/2A blocker did not. Our data are consistent with a model in which I-LTD requires both presynaptic CB1 receptor signaling and presynaptic interneuron activity in order to shift the balance of kinase and phosphatase activity in the presynaptic terminal. This integration of signals can occur over minutes, allowing for a novel form of coincidence detection and perhaps representing a new mechanism for information processing in the brain.