Frequency-Dependent Inversion of Net Striatal Output by Endocannabinoid-Dependent Plasticity at Different Synaptic Inputs

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.