Dopaminergic Control of Corticostriatal Long-Term Synaptic Depression in Medium Spiny Neurons Is Mediated by Cholinergic Interneurons

SummaryLong-term depression (LTD) of the synapse formed between cortical pyramidal neurons and striatal medium spiny neurons is central to many theories of motor plasticity and associative learning. The induction of LTD at this synapse is thought to depend upon D2 dopamine receptors localized in the postsynaptic membrane. If this were true, LTD should be inducible in neurons from only one of the two projection systems of the striatum. Using transgenic mice in which neurons that contribute to these two systems are labeled, we show that this is not the case. Rather, in both cell types, the D2 receptor dependence of LTD induction reflects the need to lower M1 muscarinic receptor activity—a goal accomplished by D2 receptors on cholinergic interneurons. In addition to reconciling discordant tracts of the striatal literature, these findings point to cholinergic interneurons as key mediators of dopamine-dependent striatal plasticity and learning.