Endocannabinoids (eCBs) mediate short- and long-term depression of synaptic strength by retrograde transsynaptic signaling. Previous studies have suggested that an eCB mobilization or release step in the postsynaptic neuron is involved in this retrograde signaling. However, it is not known whether this release process occurs automatically upon eCB synthesis or whether it is regulated by other synaptic factors. To address this issue, we loaded postsynaptic striatal medium spiny neurons (MSNs) with the eCBs anandamide (AEA) or 2-arachidonoylglycerol and determined the conditions necessary for presynaptic inhibition. We found that presynaptic depression of glutamatergic excitatory postsynaptic currents (EPSCs) and GABAergic inhibitory postsynaptic currents (IPSCs) induced by postsynaptic eCB loading required a certain level of afferent activation that varied between the different synaptic types. Synaptic depression at excitatory synapses was temperature-dependent and blocked by the eCB membrane transport blockers, VDM11 and UCM707, but did not require activation of metabotropic glutamate receptors, l -calcium channels, nitric oxide, voltage-activated Na ⁺ channels, or intracellular calcium. Application of the CB ₁ R antagonist, AM251, after depression was established, reversed the decrease in EPSC, but not in IPSC, amplitude. Direct activation of the CB ₁ receptor by WIN 55,212-2 initiated synaptic depression that was independent of afferent stimulation. These findings indicate that retrograde eCB signaling requires a postsynaptic release step involving a transporter or carrier that is activated by afferent stimulation/synaptic activation.

Changes in synaptic strength at striatal synapses, such as long-term depression (LTD), may be involved in striatal-based learning and memory. Several molecular mechanisms have been implicated in striatal LTD, but it is not clear which mechanisms are crucial for LTD induction. We found that the activation of L-type calcium channels by 2,5-dimethyl-4-[2-(phenylmethyl)benzoyl]-¹H-pyrrole-3-carboxylic acid methylester (FPL64176), combined with modest postsynaptic depolarization and synaptic activation, is sufficient to induce robust LTD (FPL–LTD). The L-channel activator 1,4-dihydro-2,6-dimethyl-5-nitro-4-[2(trifluoromethyl)phenyl]pyridine-3-carboxylic acid methyl ester (Bay K 8644) has a similar action. FPL–LTD occludes LTD induced by high-frequency stimulation (HFS–LTD) and requires elevated postsynaptic calcium and retrograde endocannabinoid signaling, properties similar to those of HFS–LTD. In contrast, FPL–LTD does not require the activation of metabotropic glutamate receptors (mGluRs), phospholipase C, or dopamine D₂ receptors. FPL–LTD induction also requires afferent stimulation. These findings suggest a scenario in which L-type calcium channel activation is a crucial switch for LTD induction, and mGluRs and D₂ receptors can be bypassed if this channel is activated.

Understanding how striatal neurons integrate glutamatergic and GABAergic inputs is essential for understanding the control of movement and the formation of striatal-based memories. Here we show that GABAergic synapses on striatal medium spiny neurons (MSNs) are more sensitive than glutamatergic synapses on the same cells to endocannabinoid (eCB) signaling, and that protocols that induce short-lasting cannabinoid 1 receptor (CB₁R)-dependent depression at glutamatergic synapses are sufficient to induce long-term depression (LTD) at GABAergic synapses. We also show that the frequency and duration of glutamatergic input are strong determinants of the net effect of eCB signaling, and key factors in determining if LTD has a net disinhibitory or inhibitory action in striatum. Plastic changes in net output from striatal MSNs are thus a complex function of disinhibitory and inhibitory LTD combined with other forms of synaptic plasticity such as long-term potentiation at excitatory synapses.