Figure 10.

Diagram of the HCN3-Associated Cellular Mechanisms Underlying the Activation of OT Neurons and its Malfunction. (A) Normal mother–baby interaction activates OTR and its downstream signals like pERK1/2 and cyclooxygenase-2. Cyclooxygenase-2 increases PGE₂ production that activates PG receptor (EP) and then the HCN3, likely mediated by cAMP that can bind to cyclic nucleotide-binding domain site of HCN3. The activation of HCN3 causes burst discharge through a rebound excitation. (B) PD causes increases in hypothalamic release of oxytocin that abnormally activates OTR. The overactivation of OTR also causes its internalization and increases molecular association with HCN3 in the cytosolic compartment. This subsequently downregulates cyclooxygenase-2 and HCN3, resulting in failure of burst discharge. The loss of burst discharge ability reduces oxytocin release into the brain and blood, thereby causing the reduction of maternal interest to the offspring, anxiety, and hypogalactia.

OT = oxytocin; Cox-2 = cyclooxygenase-2; PGE₂ = prostaglandin E₂; OTR = oxytocin receptor; cAMP = cyclic adenosine monophosphate; pERK1/2 = phosphorylated extracellular signal-regulated protein kinase1/2; HCN3 = hyperpolarization-activated cyclic nucleotide-gated channel 3; cPKA = catalytic subunit of protein kinase A.