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

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 α-methyl 5-HT (a 5-HT(1)/5-HT(2) 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-HT(1A) receptors in lumbar spinal MNs at P5. Fewer HI MNs expressed the 5-HT(1A) receptor compared to age-matched controls. This suggests many HI MNs lack a normal mechanism of central fatigue mediated by 5-HT(1A) receptors. Other 5-HT receptors (including 5-HT(2)) 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.