Mu and Delta Opioid Receptors Modulate Inhibition within the Prefrontal Cortex through Dissociable Cellular and Molecular Mechanisms

Aberrant signaling within cortical inhibitory microcircuits has been identified as a common signature of neuropsychiatric disorders. Interneuron (IN) activity is precisely regulated by neuromodulatory systems that evoke widespread changes in synaptic transmission and principal cell output. Cortical interneurons express high levels of Mu and Delta opioid receptors (MOR and DOR), positioning opioid signaling as a critical regulator of inhibitory transmission. However, we lack a complete understanding of how MOR and DOR regulate prefrontal cortex (PFC) microcircuitry. Here, we combine whole-cell patch-clamp electrophysiology, optogenetics, and viral tools to provide an extensive characterization MOR and DOR regulation of inhibitory transmission. We show that DOR activation is more effective at suppressing spontaneous inhibitory transmission in the prelimbic PFC, while MOR causes a greater acute suppression of electrically-evoked GABA release. Cell type-specific optogenetics revealed that MOR and DOR differentially regulate inhibitory transmission from parvalbumin, somatostatin, cholecystokinin, and vasoactive intestinal peptide-expressing INs. Finally, we demonstrate that DOR regulates inhibitory transmission through pre- and postsynaptic modifications to IN physiology, whereas MOR function is predominantly observed in somato-dendritic or presynaptic compartments depending on cell type. Significance StatementThe endogenous opioid system regulates behaviors that rely on prefrontal cortex (PFC) function. Previous studies have described Mu and Delta opioid receptor expression within cortical GABAergic interneurons, but a detailed understanding of how opioids regulate different interneuron subtypes and cortical microcircuits has not been reported. We use whole-cell patch-clamp electrophysiology, genetically engineered mice, and optogenetics to assess MOR and DOR regulation of PFC inhibitory transmission, demonstrating that MOR and DOR inhibition of interneurons display qualitative and quantitative variation across GABAergic circuits within mouse prelimbic PFC.