{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:37:54Z","timestamp":1792805874762,"version":"4.5.0"},"reference-count":95,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2023,8,16]],"date-time":"2023-08-16T00:00:00Z","timestamp":1692144000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P20GM103430"],"award-info":[{"award-number":["P20GM103430"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2023,10]]},"abstract":"\n Abstract<\/jats:title>\n \n Cerebral palsy (CP) is caused by a variety of factors that damage the developing central nervous system. Impaired motor control, including muscle stiffness and spasticity, is the hallmark of spastic CP. Rabbits that experience hypoxic\u2010ischaemic (HI) injury\n in utero<\/jats:italic>\n (at 70%\u201383% gestation) are born with muscle stiffness, hyperreflexia and, as recently discovered, increased 5\u2010HT in the spinal cord. To determine whether serotonergic modulation of spinal motoneurons (MNs) contributes to motor deficits, we performed\n ex vivo<\/jats:italic>\n whole cell patch clamp in neonatal rabbit spinal cord slices at postnatal day (P) 0\u20135. HI MNs responded to the application of \u03b1\u2010methyl 5\u2010HT (a 5\u2010HT\n 1<\/jats:sub>\n \/5\u2010HT\n 2<\/jats:sub>\n receptor agonist) and citalopram (a selective 5\u2010HT reuptake inhibitor) with increased amplitude and hyperpolarization of persistent inward currents and hyperpolarized threshold voltage for action potentials, whereas control MNs did not exhibit any of these responses. Although 5\u2010HT similarly modulated MN properties of HI motor\u2010unaffected and motor\u2010affected kits, it affected sag\/hyperpolarization\u2010activated cation current (\n I<\/jats:italic>\n h<\/jats:sub>\n ) and spike frequency adaptation only in HI motor\u2010affected MNs. To further explore the differential sensitivity of MNs to 5\u2010HT, we performed immunostaining for inhibitory 5\u2010HT\n 1A<\/jats:sub>\n receptors in lumbar spinal MNs at P5. Fewer HI MNs expressed the 5\u2010HT\n 1A<\/jats:sub>\n receptor compared to age\u2010matched control MNs. This suggests that HI MNs may lack a normal mechanism of central fatigue, mediated by 5\u2010HT\n 1A<\/jats:sub>\n receptors. Altered expression of other 5\u2010HT receptors (including 5\u2010HT\n 2<\/jats:sub>\n ) likely also contributes to the robust increase in HI MN excitability. In summary, by directly exciting MNs, the increased concentration of spinal 5\u2010HT in HI\u2010affected rabbits can cause MN hyperexcitability, muscle stiffness and spasticity characteristic of CP. Therapeutic strategies that target serotonergic neuromodulation may be beneficial to individuals with CP.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n We used whole cell patch clamp electrophysiology to test the responsivity of spinal motoneurons (MNs) from neonatal control and hypoxia\u2010ischaemia (HI) rabbits to 5\u2010HT, which is elevated in the spinal cord after prenatal HI injury.<\/jats:p>\n <\/jats:list-item>\n \n HI rabbit MNs showed a more robust excitatory response to 5\u2010HT than control rabbit MNs, including hyperpolarization of the persistent inward current and threshold voltage for action potentials.<\/jats:p>\n <\/jats:list-item>\n \n \n Although most MN properties of HI motor\u2010unaffected and motor\u2010affected kits responded similarly to 5\u2010HT, 5\u2010HT caused larger sag\/hyperpolarization\u2010activated cation current (\n I<\/jats:italic>\n h<\/jats:sub>\n ) and altered repetitive firing patterns only in HI motor\u2010affected MNs.\n <\/jats:p>\n <\/jats:list-item>\n \n \n Immunostaining revealed that fewer lumbar MNs expressed inhibitory 5\u2010HT\n 1A<\/jats:sub>\n receptors in HI rabbits compared to controls, which could account for the more robust excitatory response of HI MNs to 5\u2010HT.\n <\/jats:p>\n <\/jats:list-item>\n \n These results suggest that elevated 5\u2010HT after prenatal HI injury could trigger a cascade of events that lead to muscle stiffness and altered motor unit development.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp284803","type":"journal-article","created":{"date-parts":[[2023,8,19]],"date-time":"2023-08-19T01:47:59Z","timestamp":1692409679000},"page":"4271-4289","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Spinal motoneurons respond aberrantly to serotonin in a rabbit model of cerebral 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