Serotonin facilitates a persistent calcium current in motoneurons of rats with and without chronic spinal cord injury.

In the months after spinal cord transection, motoneurons in the rat spinal cord develop large persistent inward currents (PICs) that are responsible for muscle spasticity. These PICs are mediated by low-threshold TTX-sensitive sodium currents (Na PIC) and L-type calcium currents (Ca PIC). Recently, the Na PIC was shown to become supersensitive to serotonin (5-HT) after chronic injury. In the present paper, a similar change in the sensitivity of the Ca PIC to 5-HT was investigated after injury. The whole sacrocaudal spinal cord from acute spinal rats and spastic chronic spinal rats (S2 level transection 2 mo previously) was studied in vitro. Intracellular recordings were made from motoneurons and slow voltages ramps were applied to measure PICs. TTX was used to block the Na PIC. For motoneurons of chronic spinal rats, a low dose of 5-HT (1 microM) significantly lowered the threshold of the Ca PIC from -56.7 +/- 6.0 to -63.1 +/- 7.1 mV and increased the amplitude of the Ca PIC from 2.4 +/- 1.0 to 3.0 +/- 0.73 nA. Higher doses of 5-HT acted similarly. For motoneurons of acute spinal rats, low doses of 5-HT had no significant effects, whereas a high dose (about 30 microM) significantly lowered the threshold of the L-Ca PIC from -58.5 +/- 14.8 to -62.5 +/- 3.6 mV and increased the amplitude of the Ca PIC from 0.69 +/- 1.05 to 1.27 +/- 1.1 nA. Thus Ca PICs in motoneurons are about 30-fold supersensitive to 5-HT in chronic spinal rats. The 5-HT-induced facilitation of the Ca PIC was blocked by nimodipine, not by the I(h) current blocker Cs(+) (3 mM) or the SK current blocker apamin (0.15 microM), and it lasted for hours after the removal of 5-HT from the nCSF, even increasing initially after removing 5-HT. The effects of 5-HT make motoneurons more excitable and ultimately lead to larger, more easily activated plateaus and self-sustained firing. The supersensitivity to 5-HT suggests the small amounts of endogenous 5-HT below the injury in a chronic spinal rat may act on supersensitive receptors to produce large Ca PICs and ultimately enable muscle spasms.

[1]  M. Gorassini,et al.  Evidence for plateau potentials in tail motoneurons of awake chronic spinal rats with spasticity. , 2001, Journal of neurophysiology.

[2]  P Ashby,et al.  The Evaluation of “Spasticity” , 1987, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[3]  H. Barbeau,et al.  Progressive increase of motor activity induced by 5-HTP in the rat below a complete section of the spinal cord , 1979, Brain Research.

[4]  X. Li,et al.  5-HT2 receptor activation facilitates a persistent sodium current and repetitive firing in spinal motoneurons of rats with and without chronic spinal cord injury. , 2006, Journal of neurophysiology.

[5]  S. Hochman,et al.  Serotonin 5‐HT2 receptor activation induces a long‐lasting amplification of spinal reflex actions in the rat , 2001, The Journal of physiology.

[6]  X. Li,et al.  Persistent sodium currents and repetitive firing in motoneurons of the sacrocaudal spinal cord of adult rats. , 2006, Journal of neurophysiology.

[7]  P. Branchereau,et al.  Descending 5-Hydroxytryptamine Raphe Inputs Repress the Expression of Serotonergic Neurons and Slow the Maturation of Inhibitory Systems in Mouse Embryonic Spinal Cord , 2002, The Journal of Neuroscience.

[8]  M. Siu,et al.  Plateau potentials in sacrocaudal motoneurons of chronic spinal rats, recorded in vitro. , 2001, Journal of neurophysiology.

[9]  M. Mayer,et al.  A voltage‐clamp analysis of inward (anomalous) rectification in mouse spinal sensory ganglion neurones. , 1983, The Journal of physiology.

[10]  C. Henderson,et al.  Role of WHO. , 1982, Experientia. Supplementum.

[11]  C. Heckman.  Alterations in synaptic input to motoneurons during partial spinal cord injury. , 1994, Medicine and science in sports and exercise.

[12]  Brent Fedirchuk,et al.  Monoamines increase the excitability of spinal neurones in the neonatal rat by hyperpolarizing the threshold for action potential production , 2004, The Journal of physiology.

[13]  Jaynie F. Yang,et al.  Role of motoneurons in the generation of muscle spasms after spinal cord injury. , 2004, Brain : a journal of neurology.

[14]  D. Bennett,et al.  Persistent sodium and calcium currents cause plateau potentials in motoneurons of chronic spinal rats. , 2003, Journal of neurophysiology.

[15]  R. Hamill,et al.  The morphology and distribution of rat serotoninergic intraspinal neurons: An immunohistochemical study , 1988, Brain Research Bulletin.

[16]  J. Perrier,et al.  Synaptic Release of Serotonin Induced by Stimulation of the Raphe Nucleus Promotes Plateau Potentials in Spinal Motoneurons of the Adult Turtle , 2005, The Journal of Neuroscience.

[17]  X. Li,et al.  Apamin-sensitive calcium-activated potassium currents (SK) are activated by persistent calcium currents in rat motoneurons. , 2007, Journal of neurophysiology.

[18]  X. Li,et al.  5-HT 2 Receptor Activation Facilitates a Persistent Sodium Current and Repetitive Firing in Spinal Motoneurons of Rats With and Without Chronic Spinal Cord Injury , 2006 .

[19]  J. Hounsgaard,et al.  Spinal plasticity mediated by postsynaptic L-type Ca2+ channels , 2002, Brain Research Reviews.

[20]  Jørn Hounsgaard,et al.  Subcellular distribution of L‐type Ca2+ channels responsible for plateau potentials in motoneurons from the lumbar spinal cord of the turtle , 2003, The European journal of neuroscience.

[21]  C. Hulsebosch,et al.  Changes in Serotonin, Serotonin Transporter Expression and Serotonin Denervation Supersensitivity: Involvement in Chronic Central Pain after Spinal Hemisection in the Rat , 2002, Experimental Neurology.

[22]  M. Gorassini,et al.  Role of persistent sodium and calcium currents in motoneuron firing and spasticity in chronic spinal rats. , 2004, Journal of neurophysiology.

[23]  X. Li,et al.  Spastic long-lasting reflexes of the chronic spinal rat studied in vitro. , 2004, Journal of neurophysiology.

[24]  C. Heckman,et al.  Influence of voltage-sensitive dendritic conductances on bistable firing and effective synaptic current in cat spinal motoneurons in vivo. , 1996, Journal of neurophysiology.

[25]  Hans Hultborn,et al.  Key mechanisms for setting the input-output gain across the motoneuron pool. , 2004, Progress in brain research.

[26]  M. Gorassini,et al.  Spasticity in rats with sacral spinal cord injury. , 1999, Journal of neurotrauma.

[27]  J. Munson,et al.  Stretch Hyperreflexia of Triceps Surae Muscles in the Conscious Cat after Dorsolateral Spinal Lesions , 1997, The Journal of Neuroscience.

[28]  J. Hounsgaard,et al.  5-HT2 receptors promote plateau potentials in turtle spinal motoneurons by facilitating an L-type calcium current. , 2003, Journal of neurophysiology.

[29]  D. Maxwell,et al.  A confocal microscopic survey of serotoninergic axons in the lumbar spinal cord of the rat: co-localization with glutamate decarboxylase and neuropeptides , 1996, Neuroscience.

[30]  THE PHYSIOLOGY OF SENSORY CELLS IN THE VENTRAL SCOLOPARIUM OF THE STICK INSECT FEMORAL CHORDOTONAL ORGAN , 1994, The Journal of experimental biology.

[31]  H. Barbeau,et al.  Action of 5-Hydroxytryptamine, Substance P, Thyrotropin-Releasing Hormone and Clonidine on Motoneurone Excitability , 1987, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[32]  T. Nakajima,et al.  [Serotonin (5-HT)]. , 1978, Nihon rinsho. Japanese journal of clinical medicine.

[33]  C. Heckman,et al.  Enhancement of bistability in spinal motoneurons in vivo by the noradrenergic alpha1 agonist methoxamine. , 1999, Journal of neurophysiology.

[34]  X. Li,et al.  Endogenous monoamine receptor activation is essential for enabling persistent sodium currents and repetitive firing in rat spinal motoneurons. , 2006, Journal of neurophysiology.

[35]  A. Ward.  A summary of spasticity management--a treatment algorithm. , 2002, European journal of neurology.