Oxytocin-Modulated Ion Channel Ensemble Controls Depolarization, Integration and Burst Firing in CA2 Pyramidal Neurons

Oxytocin (OXT) and OXT receptor (OXTR)-mediated signaling control excitability, firing patterns, and plasticity of hippocampal CA2 pyramidal neurons, which are pivotal in generation of brain oscillations and social memory. Nonetheless, the ionic mecha-nisms underlying OXTR-induced effects in CA2 neurons are not fully understood. Using slice physiology in a reporter mouse line and interleaved current-clamp and voltage-clamp experiments, we systematically identified the ion channels modulated by OXT signaling in CA2 pyramidal cells (PYRs) in mice of both sexes and explored how changes in channel conductance support altered electrical activity. Activation of OXTRs inhibits an outward potassium current mediated by inward rectifier potassium channels (IKir) and thus favoring membrane depolarization. Concomitantly, OXT signaling also diminishes inward current medi-ated by hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels (Ih), providing a hyperpolarizing drive. The com-bined reduction in both IKirand Ih synergistically elevate the membrane resistance and favor dendritic integration while the membrane potential is restrained from quickly depolarizing from rest. As a result, the responsiveness of CA2 PYRs to synaptic inputs is highly sharpened during OXTR activation. Unexpectedly, OXTR signaling also strongly enhances a tetrodotoxin-resist-ant (TTX-R), voltage-gated sodium current that helps drive the membrane potential to spike threshold and thus promote rhyth-mic firing. This novel array of OXTR-stimulated ionic mechanisms operates in close coordination and underpins OXT-induced burst firing, a key step in CA2 PYRs' contribution to hippocampal information processing and broader influence on brain cir-cuitry. Our study deepens our understanding of underpinnings of OXT-promoted social memory and general neuropeptidergic control of cognitive states.

Automated summary

Oxytocin modulates ion channels in CA2 pyramidal neurons, increasing responsiveness to synaptic inputs and promoting rhythmic firing. These mechanisms deepen our understanding of oxytocin's role in promoting social memory and cognitive control.