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

Abstract

Background and Purpose: 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) behaviors. 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. Experimental Approach: We evaluated the mechanisms of induction of MOR-LTD and MOR-STD in the DLS using pharmacology and optogenetics combined with patch clamp electrophysiology. To evaluate glutamatergic synapses, we used C57BL/6J (all glutamatergic inputs or targeted probing of AIC-DLS inputs), Emx1-Ai32 (cortical inputs), VGluT2-Ai32 (thalamic inputs) and HCN1-flox (AIC-DLS HCN1 deletion) mice. Key Results: We found that cAMP/PKA signaling and protein synthesis are necessary for MOR-LTD expression, similar to previous studies of endocannabinoid-mediated LTD (eCB-LTD) in DLS. However, MOR-LTD does not require mTOR signaling as eCB-LTD does. MOR-STD does not utilize these same mechanisms. We characterized a novel role of presynaptic HCN1 channels in MOR-LTD induction as HCN1 channels expressed in AIC are necessary for MOR-LTD expression in the DLS. Conclusion and Implications: These results show a novel mechanism in which MOR activation needs 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.