Interneuronal Nitric Oxide Signaling Mediates Post-synaptic Long-Term Depression of Striatal Glutamatergic Synapses

• Activation of PLTS interneurons produces NO-LTD at SPN glutamatergic synapses
• NO-LTD is dependent upon cGMP signaling and expressed postsynaptically
• NO-LTD is independent of activity and the origin of presynaptic terminal
• NO blunts presynaptic eCb-LTD by suppressing dendritic L-type Ca2+ channels

SummaryExperience-driven plasticity of glutamatergic synapses on striatal spiny projection neurons (SPNs) is thought to be essential to goal-directed behavior and habit formation. One major form of striatal plasticity, long-term depression (LTD), has long appeared to be expressed only pre-synaptically. Contrary to this view, nitric oxide (NO) generated by striatal interneurons was found to induce a post-synaptically expressed form of LTD at SPN glutamatergic synapses. This form of LTD was dependent on signaling through guanylyl cyclase and protein kinase G, both of which are abundantly expressed by SPNs. NO-LTD was unaffected by local synaptic activity or antagonism of endocannabinoid (eCb) and dopamine receptors, all of which modulate canonical, pre-synaptic LTD. Moreover, NO signaling disrupted induction of this canonical LTD by inhibiting dendritic Ca2+ channels regulating eCb synthesis. These results establish an interneuron-dependent, heterosynaptic form of post-synaptic LTD that could act to promote stability of the striatal network during learning.

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