Activation of Oxytocin Receptors Excites Subicular Neurons by Multiple Signaling and Ionic Mechanisms

Abstract

Oxytocin (OXT) is a nonapeptide that serves as a neuromodulator in the brain and a hormone participating in parturition and lactation in the periphery. The subiculum is the major output region of the hippocampus and an integral component in the networks that process sensory and motor cues to form a cognitive map encoding spatial, contextual, and emotional information. Whilst the subiculum expresses the highest OXT-binding sites and is the first brain region to be activated by peripheral application of OXT, the precise actions of OXT in the subiculum have not been determined. Our results demonstrate that application of the selective OXT receptor (OXTR) agonist, [Thr4,Gly7]-oxytocin (TGOT), excited subicular neurons via activation of TRPV1 channels, and depression of K+ channels. The OXTR-mediated excitation of subicular neurons required the functions of phospholipase Cβ, protein kinase C, and degradation of phosphatidylinositol 4,5-bisphosphate (PIP2). OXTR-elicited excitation of subicular neurons enhanced long-term potentiation via activation of TRPV1 channels. Our results provide a cellular and molecular mechanism to explain the physiological functions of OXT in the brain.

Oxytocin-modulated ion channel ensemble controls depolarization, integration and burst firing in CA2 pyramidal neurons

“…OXT-/vasopressin-like nonapeptides exemplify peptide neuromodulators conserved across invertebrate and vertebrate taxa ( Bargmann and Marder, 2013 ; Jurek and Neumann, 2018 ; Theofanopoulou et al, 2021 ). OXT generally depolarizes target cells by inducing a net inward current, with varied ionic mechanisms suggested ( Owen et al, 2013 ; Jiang et al, 2014 ; Tang et al, 2014 ; Briffaud et al, 2015 ; Tirko et al, 2018 ; Maniezzi et al, 2019 ; Hu et al, 2020 , 2021 ; Zhang et al, 2021 ). CA2 PYRs provided a suitable testbed for evaluation of potential target mechanisms with interleaved current clamp and voltage clamp recordings and well-characterized pharmacological agents.…”

“…Mammals express a single gene encoding the OXT receptor (OXTR), a G (guanine nucleotide-binding) protein-coupled receptor widely expressed in the brain ( Mitre et al, 2016 ). Activation of OXTR generally depolarizes target cells and induces a variety of effects on synaptic transmission, with varied signaling cascades and ionic mechanisms suggested ( Tomizawa et al, 2003 ; Wang and Hatton, 2007 ; Owen et al, 2013 ; Jiang et al, 2014 ; Tang et al, 2014 ; Briffaud et al, 2015 ; Tirko et al, 2018 ; Maniezzi et al, 2019 ; Hu et al, 2020 , 2021 ; Zhang et al, 2021 ). In the HP, OXTRs express at high levels in the CA2 and CA3a subregions ( Mitre et al, 2016 ; Tirko et al, 2018 ).…”

Neuromodulatory functions exerted by oxytocin on different populations of hippocampal neurons in rodents

“…At these synapses OT contributes to the maintenance of the late phase of LTP, but not to the early phase (Lin et al, 2012). An OT-dependent enhancement of LTP has also been reported at CA1-subiculum synapses (Hu et al, 2021).…”

“…These two effects improve the fidelity and temporal precision of the information transfer through this area. Pekarek et al, 2020;Hu et al, 2021). OT application on cultured glutamatergic hippocampal neurons drives dendritic and synaptic remodeling confirming that plasticity processes occur at these synapses (Ripamonti et al, 2017).…”

“…Differences in receptor expression are observed in relation both to the hippocampal subregions and to different neuronal subtypes (Table 1). In the dentate gyrus (DG), OTRs are present almost exclusively in the region of hilus, where they are expressed by the GABAergic interneurons (INs) and, to a lesser extent, by the excitatory mossy cells (Lin et al, 2017;Raam et al, 2017;10.3389/fncel.2023.1082010 Raggenbass et al, 1989Hu et al, 2021 Bibliographical references for each area are reported. Meyer et al, 2020;Bertoni et al, 2021).…”