Divergent opioid-medifated suppression of inhibition between hippocampus and neocortex across species and development

Abstract

Opioid receptors within the CNS regulate pain sensation and mood and are key targets for drugs of abuse. Within the adult rodent hippocampus (HPC), μ-opioid receptor agonists suppress inhibitory parvalbumin-expressing interneurons (PV-INs), thus disinhibiting the circuit. However, it is uncertain if this disinhibitory motif is conserved in other cortical regions, species, or across development. We observed that PV-IN mediated inhibition is robustly suppressed by opioids in HPC but not neocortex in mice and nonhuman primates, with spontaneous inhibitory tone in resected human tissue also following a consistent dichotomy. This hippocampal disinhibitory motif was established in early development when immature PV-INs and opioids already influence primordial network rhythmogenesis. Acute opioid-mediated modulation was partially occluded with morphine pretreatment, with implications for the effects of opioids on hippocampal network activity during circuit maturation as well as learning and memory. Together, these findings demonstrate that PV-INs exhibit a divergence in opioid sensitivity across brain regions that is remarkably conserved across evolution and highlights the underappreciated role of opioids acting through immature PV-INs in shaping hippocampal development.

Maternal Immune Activation Alters Temporal Precision of Spike Generation of CA1 Pyramidal Neurons by Unbalancing GABAergic Inhibition in the Offspring

“…Membrane potential was held at 0 mV, and APV (50 µM) was added to the bath perfusion to isolate the outward GABAergic currents. We took advantage of the selective expression of mu receptors (MOR) and cannabinoid receptor 1 (CB1R) in parvalbumin-expressing interneurons (PV-IN) and cholecystokinin-expressing interneurons (CCK-IN), respectively (Caccavano et al, 2024; Heifets et al, 2008; Monday et al, 2020) to analyze the effect of MIA on the selective inhibition from these two subpopulations of interneurons. Following a baseline recording, the selective MOR agonist DAMGO (2 µM) or the selective CB1R agonist WIN 55, 212 (2 µM) was added to the bath perfusion.…”