The role of oxytocin in the hippocampal synaptic plasticity and adult neurogenesis

Abstract

In addition to involvement in parturition and lactation oxytocin (OXT) has been shown to regulate a wide variety of behaviors Given that OXT receptors (OXTR) are expressed in the hippocampus and oxytocin neurons of the paraventricular nucleus also send substantial projections to the hippocampus we attempt to identify the role of oxytocin in the hippocampal synaptic plasticity and adult neurogenesis In term of the effect on the synaptic plasticity we demonstrate that OXT promotes the maintenance of long-term potentiation (LTP) induced by one train of tetanic stimulation in the CA1 region of hippocampal slices from both nulliparous female and male rats through a previously unknown mechanism involving OXTR-dependent and epidermal growth factor receptor (EGFR)-mediated pathway Using electrophysiological and biochemical approaches we show that the conventional OXTR-associated signaling pathway transactivates EGFR downstream signaling pathways and stimulates local dendritic translation of an atypical protein kinase C isoform protein kinase Mζ (PKMζ) These results reveal a novel OXTR-to-EGFR communication to regulate the new synthesis of PKMζ which functions to promote the maintenance of LTP at hippocampal CA1 synapses Apart from regulation of synaptic plasticity we also show that endogenous OXT signaling controls adult neurogenesis through a non-cell-autonomous mechanism by OXT receptors (OXTR) expressed in CA3 pyramidal neurons Conditional deletion of OXTR (OXTR-/-) from excitatory neurons not only decreases the number of survival newborn neurons but also delays morphological and functional development of those survived newborn neurons In the hippocampal dependent spatial memory task OXTR-/- mice also show impairment when compared with wild type mice Retrograde neuronal tracing combined with immunocytochemistry further comfirm that the OXT neurons in the paraventricular nucleus project directly to the CA3 region of the hippocampus In addition bath application of OXT elicited a membrane depolarization and increased action potential firing in OXTR-expressing CA3 pyramidal neurons Using adenoviral-mediated expression of engineered Gi/o-coupled human M4 (hM4Di) receptors we observe that activation of hM4Di receptors with clozapine-N-oxide (CNO) reduces CA3 pyramidal neuron activity and resultes in fewer newly DGCs in Floxed OXTR mice Conversely CNO-induced activation of Gq-coupled human M3 receptors restores adult neurogenesis in the DG of OXTR-/- mice These results suggest that CA3 may regulate adult DG neurogenesis under basal conditions and OXT controls adult hippocampal neurogenesis via OXTR expressed in CA3 pyramidal neurons Here we combine electrophysiological biochemical and behavioral studies to identify the important role of OXT in the regulation of hippocampal synaptic plasticity and adult neurogenesis

Date of Award	2016 Jul 5
Original language	English
Supervisor	Kuei-Sen Hsu (Supervisor)