Phoenixin-14 (PNX-14) has a wide bioactivity in the central nervous system. Its role in the hypothalamus has been investigated, and it has been reported that it is involved in the regulation of excitability in hypothalamic neurons. However, its role in the regulation of excitability in entorhinal cortex and the hippocampus is unknown. In this study, we investigated whether i. PNX-14 induces any synchronous discharges or epileptiform activity and ii. PNX-14 has any effect on already initiated epileptiform discharges. We used 350 µm thick acute horizontal hippocampal–entorhinal cortex slices obtained from 30- to 35-day-old mice. Extracellular field potential recordings were evaluated in the entorhinal cortex and hippocampus CA1 region. Bath application of PNX-14 did not initiate any epileptiform activity or abnormal discharges. 4-Aminopyridine was applied to induce epileptiform activity in the slices. We found that 200 nM PNX-14 reduced the frequency of interictal-like events in both the entorhinal cortex and hippocampus CA1 region which was induced by 4-aminopyridine. Furthermore, PNX-14 led to a similar suppression in the total power of local field potentials of 1–120 Hz. The frequency or the duration of the ictal events was not affected. These results exhibited for the first time that PNX-14 has a modulatory effect on synchronized neuronal discharges which should be considered in future therapeutic approaches.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price includes VAT (USA)
Tax calculation will be finalised during checkout.
Abidin İ, Aydin-Abidin S, Mittmann T (2019) Neuronal excitability and spontaneous synaptic transmission in the entorhinal cortex of BDNF heterozygous mice. Neurosci Lett 690:69–75. https://doi.org/10.1016/j.neulet.2018.10.019
Avoli M, Jefferys JGR (2016) Models of drug-induced epileptiform synchronization in vitro. J Neurosci Methods 260:26–32. https://doi.org/10.1016/j.jneumeth.2015.10.006
Avoli M, D’Antuono M, Louvel J et al (2002) Network and pharmacological mechanisms leading to epileptiform synchronization in the limbic system in vitro. Prog Neurobiol 68:167–207. https://doi.org/10.1016/S0301-0082(02)00077-1
Aydin-Abidin S, Abidin İ (2019) 7,8-Dihydroxyflavone potentiates ongoing epileptiform activity in mice brain slices. Neurosci Lett 703:25–31. https://doi.org/10.1016/j.neulet.2019.03.013
Bell KA, Delong R, Goswamee P, McQuiston AR (2021) The entorhinal cortical alvear pathway differentially excites pyramidal cells and interneuron subtypes in hippocampal CA1. Cereb Cortex 31:2382–2401. https://doi.org/10.1093/cercor/bhaa359
Binder DK, Steinhäuser C (2021) Astrocytes and epilepsy. Neurochem Res. https://doi.org/10.1007/s11064-021-03236-x
Brückner C, Heinemann U (2000) Effects of standard anticonvulsant drugs on different patterns of epileptiform discharges induced by 4-aminopyridine in combined entorhinal cortex–hippocampal slices. Brain Res 859:15–20. https://doi.org/10.1016/S0006-8993(99)02348-3
Chang M, Dian JA, Dufour S et al (2018) Brief activation of GABAergic interneurons initiates the transition to ictal events through post-inhibitory rebound excitation. Neurobiol Dis 109:102–116. https://doi.org/10.1016/j.nbd.2017.10.007
Coetzee WA, Amarillo Y, Chiu J et al (1999) Molecular diversity of K+ channels. Ann N Y Acad Sci 868:233–255. https://doi.org/10.1111/j.1749-6632.1999.tb11293.x
Dingledine R, Dodd J, Kelly JS (1980) The in vitro brain slice as a useful neurophysiological preparation for intracellular recording. J Neurosci Methods 2:323–362. https://doi.org/10.1016/0165-0270(80)90002-3
Ferguson AV, Latchford KJ, Samson WK (2008) The paraventricular nucleus of the hypothalamus – a potential target for integrative treatment of autonomic dysfunction. Expert Opin Ther Targets 12:717–727. https://doi.org/10.1517/14728220.127.116.117
Fueta Y, Avoli M (1992) Effects of antiepileptic drugs on 4-aminopyridine-induced epileptiform activity in young and adult rat hippocampus. Epilepsy Res 12:207–215. https://doi.org/10.1016/0920-1211(92)90075-5
Gasparini S, Stein LM, Loewen SP et al (2018) Novel regulator of vasopressin secretion: phoenixin. Am J Physiol Regul Integr Comp Physiol 314:R623–R628. https://doi.org/10.1152/ajpregu.00426.2017
Gonzalez-Sulser A, Wang J, Motamedi GK et al (2011) The 4-aminopyridine in vitro epilepsy model analyzed with a perforated multi-electrode array. Neuropharmacology 60:1142–1153. https://doi.org/10.1016/j.neuropharm.2010.10.007
Gonzalez-Sulser A, Wang J, Queenan BN et al (2012) Hippocampal neuron firing and local field potentials in the in vitro 4-aminopyridine epilepsy model. J Neurophysiol 108:2568–2580. https://doi.org/10.1152/jn.00363.2012
Kinboshi M, Ikeda A, Ohno Y (2020) Role of astrocytic inwardly rectifying potassium (Kir) 4.1 channels in Epileptogenesis. Front Neurol. https://doi.org/10.3389/fneur.2020.626658
Kovac S, Walker MC (2013) Neuropeptides in epilepsy. Neuropeptides 47:467–475. https://doi.org/10.1016/j.npep.2013.10.015
Ledri M, Sorensen AT, Madsen MG et al (2015) Differential effect of neuropeptides on excitatory synaptic transmission in human epileptic hippocampus. J Neurosci 35:9622–9631. https://doi.org/10.1523/JNEUROSCI.3973-14.2015
Lyu R-M, Huang X-F, Zhang Y et al (2013) Phoenixin: a novel peptide in rodent sensory ganglia. Neuroscience 250:622–631. https://doi.org/10.1016/j.neuroscience.2013.07.057
Ma H, Su D, Wang Q et al (2020) Phoenixin 14 inhibits ischemia/reperfusion-induced cytotoxicity in microglia. Arch Biochem Biophys 689:108411. https://doi.org/10.1016/j.abb.2020.108411
Mcilwraith EK, Belsham DD (2018) Phoenixin: uncovering its receptor, signaling and functions. Acta Pharmacol Sin 39:774–778. https://doi.org/10.1038/aps.2018.13
Nguyen XP, Nakamura T, Osuka S et al (2019) Effect of the neuropeptide phoenixin and its receptor GPR173 during folliculogenesis. Reproduction 158:25–34. https://doi.org/10.1530/REP-19-0025
Pinheiro Da Silva F, MacHado MCC, Velasco IT (2013) Neuropeptides in sepsis: from brain pathology to systemic inflammation. Peptides 44:135–138. https://doi.org/10.1016/j.peptides.2013.03.029
Prinz P, Scharner S, Friedrich T et al (2017) Central and peripheral expression sites of phoenixin-14 immunoreactivity in rats. Biochem Biophys Res Commun 493:195–201. https://doi.org/10.1016/j.bbrc.2017.09.048
Qian J, Saggau P (1999) Modulation of transmitter release by action potential duration at the hippocampal CA3-CA1 synapse. J Neurophysiol 81:288–298. https://doi.org/10.1152/jn.1918.104.22.1688
Sagar SM, Flint Beal M, Marshall PE et al (1984) Implications of neuropeptides in neurological diseases. Peptides 5:255–262. https://doi.org/10.1016/0196-9781(84)90284-5
Schalla M, Stengel A (2018) Phoenixin—a pleiotropic gut-brain peptide. Int J Mol Sci 19:1726. https://doi.org/10.3390/ijms19061726
Staley KJ, Dudek FE (2006) Interictal spikes and epileptogenesis. epilepsy. Currents 6:199–202. https://doi.org/10.1111/j.1535-7511.2006.00145.x
Stein LM, Tullock CW, Mathews SK et al (2016) Hypothalamic action of phoenixin to control reproductive hormone secretion in females: importance of the orphan G protein-coupled receptor Gpr173. Am J Physiol Regul Integr Comp Physiol 311:R489–R496. https://doi.org/10.1152/ajpregu.00191.2016
Stein LM, Haddock CJ, Samson WK et al (2018) The phoenixins: from discovery of the hormone to identification of the receptor and potential physiologic actions. Peptides 106:45–48. https://doi.org/10.1016/j.peptides.2018.06.005
Treen AK, Luo V, Belsham DD (2016) Phoenixin activates immortalized GnRH and Kisspeptin neurons through the novel receptor GPR173. Mol Endocrinol 30:872–888. https://doi.org/10.1210/me.2016-1039
van den Pol AN (2012) Neuropeptide transmission in brain circuits. Neuron 76:98–115. https://doi.org/10.1016/j.neuron.2012.09.014
Yuan T, Sun Z, Zhao W et al (2017) Phoenixin: a newly discovered peptide with multi-functions. Protein Pept Lett. https://doi.org/10.2174/0929866524666170207154417
Conflict of interest
Authors declare no conflict of interest.
Data availability statement
Our manuscript has no associated data.
The study was ethically approved and registered by Karadeniz Technical University Faculty of Medicine, experimental animal ethics committee (Protocol nr: 2020/4).
Consent for publication
All authors read and approved the final manuscript.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Communicated by Bill J Yates.
About this article
Cite this article
Kalkan, Ö.F., Şahin, Z., Öztürk, H. et al. Phoenixin-14 reduces the frequency of interictal-like events in mice brain slices. Exp Brain Res 239, 2841–2849 (2021). https://doi.org/10.1007/s00221-021-06179-5
- Extracellular recording
- Epileptiform activity
- Entorhinal cortex