Oxytocin Transforms Firing Mode of CA2 Hippocampal Neurons

Abstract

SUMMARY Oxytocin is an important neuromodulator in the mammalian brain that increases information salience and circuit plasticity, but its signaling mechanisms and circuit effect are not fully understood. Here we report robust oxytocinergic modulation of intrinsic properties and circuit operations in hippocampal area CA2, a region of emerging importance for hippocampal function and social behavior. Upon oxytocin receptor activation, CA2 pyramidal cells depolarize and fire bursts of action potentials, a consequence of phospholipase C signaling to modify two separate voltage-dependent ionic processes. A reduction of potassium current carried by KCNQ-based M channels depolarizes the cell; protein kinase C activity attenuates spike rate of rise and overshoot, dampening after-hyperpolarizations. These actions, in concert with activation of fast-spiking interneurons, promote repetitive firing and CA2 bursting; bursting then governs short-term plasticity of CA2 synaptic transmission onto CA1 and, thus, efficacy of information transfer in the hippocampal network.

Oxytocin and vasopressin in the rodent hippocampus

“…Both mechanisms, working in concert with Oxtr‐dependent enhancement of GABAergic transmission in the CA2 region (see below), promote intense short bursts of CA2 principal cells that is expected to favor robust and precise transfer of social information to downstream CA1 targets . The Oxtr‐mediated enhancement of both CA2 intrinsic excitability and excitatory input illustrate the profound modulatory effect Oxt exerts on an important component of the social memory circuit.…”

“…Dorsal oxytocinergic inputs are implicated, however, because injections of the monosynaptic retrograde tracer cholera toxin B subunit into the dorsal CA3 region labels Oxt‐positive cells within the PVN of male mice . In a more recent study, anterograde tracing of PVN‐derived Oxt input indicates that Oxt fiber density is most intense in the CA2 and CA3 regions …”

“…Selective activation of the Oxtr on CA2 pyramidal neurons transforms their firing mode by directly altering their intrinsic excitability . In ex vivo slices prepared from male mice, both optical stimulation of PVN‐derived Oxt‐expressing fibers in the CA2 region and pharmacological activation of the Oxtr induce a robust membrane depolarization sufficient to drive burst‐firing in CA2 neurons while synaptic transmission is blocked.…”

“…In ex vivo slices prepared from male mice, both optical stimulation of PVN‐derived Oxt‐expressing fibers in the CA2 region and pharmacological activation of the Oxtr induce a robust membrane depolarization sufficient to drive burst‐firing in CA2 neurons while synaptic transmission is blocked. This Oxtr‐induced change in intrinsic excitability involves a combination of both phospholipase C‐dependent inhibition of KCNQ channels, affecting the resting membrane potential, and phospholipase C‐ or protein kinase C‐dependent changes in action potential shape . Both mechanisms, working in concert with Oxtr‐dependent enhancement of GABAergic transmission in the CA2 region (see below), promote intense short bursts of CA2 principal cells that is expected to favor robust and precise transfer of social information to downstream CA1 targets .…”

“…Both Oxt‐ and Avp alter inhibitory transmission in the CA3 and CA2 regions. Although the Oxtr is abundantly expressed on excitatory neurons in the CA2 and immediately adjacent CA3 areas, the Oxtr is also present on inhibitory interneurons in mice of both sexes . Interneurons in CA2/CA3 that are responsive to Oxt might be expected to be largely located in the striatum pyramidale, as seen in the CA1 region, since Oxt does not influence the excitability of CA3 interneurons of the stratum lacunosum moleculare or stratum radiatum .…”