Disruption of endocannabinoid release and striatal long-term depression by postsynaptic blockade of endocannabinoid membrane transport.

Activation of the CB1 cannabinoid receptor inhibits neurotransmission at numerous synapses in the brain. Indeed, CB1 is essential for certain types of both short- and long-term synaptic depression. It was demonstrated recently that CB1 is critical for activity-dependent long-term depression (LTD) at glutamatergic corticostriatal synapses in acute brain slice preparations. Here, we show that CB1 activation is necessary, but not solely sufficient, for induction of LTD and that the requisite signaling by endocannabinoids (eCBs) occurs during a time window limited to the first few minutes after high-frequency stimulation delivery. In addition, we have applied intracellularly anandamide membrane transporter inhibitors to provide novel evidence that postsynaptic transport mechanisms are responsible for the release of eCBs from striatal medium spiny neurons. These findings shed new light on the mechanisms by which transient eCB formation participates in the induction of long-lasting changes in synaptic efficacy that could contribute to brain information storage.