Dual Regulation of Anterograde and Retrograde Transmission by Endocannabinoids

Abstract

Endocannabinoids (eCBs) are feedback messengers in the nervous system that act at the presynaptic nerve terminal to inhibit transmitter release. Here we report that in brain slices from rat, eCBs are released from vasopressin (VP) neurons in the paraventricular nucleus of the hypothalamus following coincident bursts of presynaptic and postsynaptic spiking. eCBs transiently depress glutamate release from excitatory terminals and, in doing so, prevent the synapses from undergoing long-term depression (LTD). Specifically, we show that blockade of CB1 receptors unmasks LTD following coincident presynaptic and postsynaptic activity. This LTD is presynaptic in nature, but requires the release of the opioid peptide dynorphin from the postsynaptic neuron. Dynorphin release and subsequent LTD require the activation of postsynaptic metabotropic glutamate receptors (mGluRs). Our findings indicate that eCBs, by transiently depressing glutamate release, limit mGluR activation and indirectly gate release of dynorphin from the postsynaptic neuron. We propose that eCBs, in addition to their well described role in the rapid modulation of transmitter release from the nerve terminal, also regulate the release of other retrograde transmitters and thus encode for multiple temporal windows of synaptic plasticity.

Opioids induce dissociable forms of long-term depression of excitatory inputs to the dorsal striatum

“…4c). In light of recent evidence of LTD in hypothalamic parvocellular neuroendocrine cells mediated by postsynaptic calcium- and mGluR-dependent opioid peptide release 15,17 , we assessed the contribution of these signaling pathways in OP-LTD. Inclusion of either the calcium chelator BAPTA (65.3 ± 4.7%) or the GDP analog GDPβS (81.5 ± 4.4%) in the intrapipette solution failed to alter peptidase inhibitor–mediated LTD (Fig.…”

Functional consequences of neuropeptide and small-molecule co-transmission

“…One pivotal insight is that different subsets of co-transmitters are released from a single neuron in response to different inputs, enabling the selective generation or regulation of different aversive behaviours. Selective regulation of peptide co-transmitter release also occurs in other systems (see below and REFS 59,60 ).…”

“…Somatodendritic DYN release produces long-term depression (LTD) of presynaptic glutamate release, reducing excitatory drive to the VP–DYN–eCB neurons 88 . A dynamic interplay exists between the retrograde actions of DYN and VP-triggered eCBs on the glutamatergic inputs 60 . Depending on the relative intensity of presynaptic and postsynaptic activity, eCB or DYN retrograde release dominates.…”

“…Depending on the relative intensity of presynaptic and postsynaptic activity, eCB or DYN retrograde release dominates. When the eCB action dominates, it acutely inhibits presynaptic glutamate release, limiting glutamate access to postsynaptic metabotropic glutamate receptors (mGluRs), the activation of which is necessary for enhanced VP and DYN release and subsequent LTD generation 60 . Consequently, eCB release indirectly inhibits release of its co-transmitters VP and DYN.…”

Presynaptic long-term depression mediated by Gi/o-coupled receptors

“…Dynorphin is somatodendritically released from vasopressin MNCs to act on presynaptic KORs. Here, KOP-LTD is gated by the presynaptic modulation of glutamate release by eCB signaling [82]. GABAergic synapses onto paraventricular neuroendocrine cells also undergo LTD when moderate frequency stimulation is paired with postsynaptic depolarization in slices treated with cortisol or in slices made from previously stressed animals [83].…”