HCN1 channels mediate mu opioid receptor long‐term depression at insular cortex inputs to the dorsal striatum

Abstract Mu opioid receptors (MORs) are expressed in the dorsal striatum, a brain region that mediates goal‐directed (via the dorsomedial striatum) and habitual (via the dorsolateral striatum, DLS) behaviours. Our previous work indicates that glutamate transmission is depressed when MORs are activated in the dorsal striatum, inducing MOR‐mediated long‐term synaptic depression (MOR‐LTD) or short‐term depression (MOR‐STD), depending on the input. In the DLS, MOR‐LTD is produced by MORs on anterior insular cortex (AIC) inputs and MOR‐STD occurs at thalamic inputs, suggesting input‐specific MOR plasticity mechanisms. Here, we evaluated the mechanisms of induction of MOR‐LTD and MOR‐STD in the DLS using pharmacology and optogenetics combined with patch‐clamp electrophysiology. We found that cAMP/PKA signalling and protein synthesis are necessary for MOR‐LTD expression, similar to previous studies of cannabinoid‐mediated LTD in DLS. MOR‐STD does not utilize these same mechanisms. We also demonstrated that cannabinoid‐LTD occurs at AIC inputs to DLS. However, while cannabinoid‐LTD requires mTOR signalling in DLS, MOR‐LTD does not. We characterized the role of presynaptic HCN1 channels in MOR‐LTD induction as HCN1 channels expressed in AIC are necessary for MOR‐LTD expression in the DLS. These results suggest a mechanism in which MOR activation requires HCN1 to induce MOR‐LTD, suggesting a new target for pharmacological modulation of synaptic plasticity, providing new opportunities to develop novel drugs to treat alcohol and opioid use disorders. image Key points Mu opioid receptor‐mediated long‐term depression at anterior insular cortex inputs to dorsolateral striatum involves presynaptic cAMP/PKA signalling and protein translation, similar to known mechanisms of cannabinoid long‐term depression. Dorsal striatal cannabinoid long‐term depression also occurs at anterior insular cortex inputs to the dorsolateral striatum. Dorsal striatal cannabinoid long‐term depression requires mTOR signalling, similar to hippocampal cannabinoid long‐term depression, but dorsal striatal mu opioid long‐term depression does not require mTOR signalling. Mu opioid long‐term depression requires presynaptic HCN1 channels at anterior insular cortex inputs to dorsolateral striatum.