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bioRxiv · 10.1101/2023.04.05.535691

Spinal motoneurons respond aberrantly to serotonin in a rabbit model of cerebral palsy

Reedich, E. J.·Genry, L. T.·Steele, P. R.·Mena Avila, E.·Dowaliby, L.·Drobyshevsky, A.·Manuel, M.·Quinlan, K. A.
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Abstract

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-ischemic (HI) injury in utero (at 70-80% gestation) are born with muscle stiffness, hyperreflexia, and, as recently discovered, increased serotonin (5-HT) in the spinal cord. To determine whether serotonergic modulation of spinal motoneurons (MNs) contributes to motor deficits, we performed ex vivo whole cell patch clamp in neonatal rabbit spinal cord slices at postnatal day (P) 0-5. HI MNs responded to application of -methyl 5-HT (a 5-HT1/5-HT2 receptor agonist) and citalopram (a selective 5-HT reuptake inhibitor) with hyperpolarization of persistent inward currents and threshold voltage for action potentials, reduced maximum firing rate, and an altered pattern of spike frequency adaptation while control MNs did not exhibit any of these responses. To further explore the differential sensitivity of MNs to 5-HT, we performed immunohistochemistry for inhibitory 5-HT1A receptors in lumbar spinal MNs at P5. Fewer HI MNs expressed the 5-HT1A receptor compared to age-matched controls. This suggests many HI MNs lack a normal mechanism of central fatigue mediated by 5-HT1A receptors. Other 5-HT receptors (including 5-HT2) are likely responsible for the robust increase in HI MN excitability. In summary, by directly exciting MNs, the increased concentration of spinal 5-HT in HI 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. Key pointsO_LIAfter prenatal hypoxia-ischemia (HI), neonatal rabbits that show hypertonia are known to have higher levels of spinal serotonin C_LIO_LIWe tested responsivity of spinal motoneurons (MNs) in neonatal control and HI rabbits to serotonin using whole cell patch clamp C_LIO_LIMNs from HI rabbits showed a more robust excitatory response to serotonin than control MNs, including hyperpolarization of the persistent inward current and threshold for action potentials, larger post-inhibitory rebound, and less spike frequency adaptation C_LIO_LIBased on immunohistochemistry of lumbar MNs, fewer HI MNs express inhibitory 5HT1A receptors than control MNs, which could account for the more robust excitatory response of HI MNs. C_LIO_LIThese results suggest that after HI injury, the increased serotonin could trigger a cascade of events leading to muscle stiffness and altered motor unit development C_LI

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Reedich, E. J., Genry, L. T., Steele, P. R., Mena Avila, E., Dowaliby, L., Drobyshevsky, A., Manuel, M., Quinlan, K. A.. 2023-04-06. Spinal motoneurons respond aberrantly to serotonin in a rabbit model of cerebral palsy. https://doi.org/10.1101/2023.04.05.535691

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