Motoneuron Excitability and Muscle Spasms Are Regulated by 5-HT<sub>2B</sub>and 5-HT<sub>2C</sub>Receptor Activity

Murray, Katherine C.; Stephens, Marilee J.; Ballou, Edmund W.; Heckman, C. J.; Bennett, David J.

doi:10.1152/jn.00774.2010

Cited by 126 publications

(137 citation statements)

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“…Consistent with these observations, 5-HT 2A Rs and 5-HT 2C Rs exert opposing effects on both locomotor activity in mice (41) and the long-lasting amplification of spinal reflexes in rats (42). Interestingly, 5-HT 2B Rs and 5-HT 2C Rs become constitutively active (spontaneously active without 5-HT) after SCI (43,44). This constitutive activity may be partly responsible for the depolarizing shift of E Cl after SCI (10).…”

Section: Discussionmentioning

confidence: 67%

“…However, motoneurons slowly recover the capacity to generate PICs, which are, in large part, responsible for longlasting reflexes and spasms (49,50). Both 5-HT 2B Rs and 5-HT 2C Rs, but not 5-HT 2A Rs, are involved in this up-regulation of PICs (44). To conclude, by restoring endogenous inhibition through an upregulation of KCC2 function, without depolarizing motoneurons and activating PICs, activation of 5-HT 2A Rs may represent an innovative therapeutic strategy to reduce spasticity after SCI.…”

Section: Discussionmentioning

confidence: 99%

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Activation of 5-HT2A receptors upregulates the function of the neuronal K-Cl cotransporter KCC2

Bos

Sadlaoud

Boulenguez

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

159

172

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In healthy adults, activation of γ-aminobutyric acid (GABA) A and glycine receptors inhibits neurons as a result of low intracellular chloride concentration ([Cl -] i ), which is maintained by the potassium-chloride cotransporter KCC2. A reduction of KCC2 expression or function is implicated in the pathogenesis of several neurological disorders, including spasticity and chronic pain following spinal cord injury (SCI). Given the critical role of KCC2 in regulating the strength and robustness of inhibition, identifying tools that may increase KCC2 function and, hence, restore endogenous inhibition in pathological conditions is of particular importance. We show that activation of 5-hydroxytryptamine (5-HT) type 2A receptors to serotonin hyperpolarizes the reversal potential of inhibitory postsynaptic potentials (IPSPs), E IPSP , in spinal motoneurons, increases the cell membrane expression of KCC2 and both restores endogenous inhibition and reduces spasticity after SCI in rats. Up-regulation of KCC2 function by targeting 5-HT 2A receptors, therefore, has therapeutic potential in the treatment of neurological disorders involving altered chloride homeostasis. However, these receptors have been implicated in several psychiatric disorders, and their effects on pain processing are controversial, highlighting the need to further investigate the potential systemic effects of specific 5-HT 2A R agonists, such as (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide (TCB-2). ] i (depolarizing shift of the chloride equilibrium potential, E Cl ) dramatically compromises the inhibitory control of firing rate and excitatory inputs (5-7). Given the role of KCC2 in regulating the strength of inhibitory synaptic transmission, identifying tools that may increase KCC2 function and, hence, restore endogenous inhibition in pathological conditions is of particular importance.Spasticity is a disabling complication affecting individuals with spinal cord injury (SCI) and is characterized by a velocity-dependent increase in muscle tone resulting from hyperexcitable stretch reflexes, spasms, and hypersensitivity to normally innocuous sensory stimulations (8, 9). Down-regulation of KCC2 after SCI in rats is implicated in the development of spasticity (10) and chronic pain (11,12). Notably, the expression of KCC2 in the motoneuron membrane is reduced, and, concomitantly, the density of cytoplasmic clusters is higher, suggesting that the surface stability of the transporter is reduced in these pathological conditions (10).Mounting evidence indicates that phosphorylation of KCC2 in the C-terminal intracellular domain dynamically regulates its activity and surface expression (1). In particular, phosphorylation by protein kinase (PK)C, enhances KCC2 activity and reduces endocytosis (13). Interestingly, activation of 5-hydroxytryptamine type 2 receptors (5-HT 2 Rs) to serotonin stimulates PKC and strengthens the left-right alternation of motor bursts observed during locomotion (14-16), which rely on reciprocal inhibition (17, 18). ...

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Activation of 5-HT2A receptors upregulates the function of the neuronal K-Cl cotransporter KCC2

Bos

Sadlaoud

Boulenguez

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

159

172

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“…The present work demonstrates the importance of dendritic SK currents in the control of PICs, suggesting that they may be an intrinsic motoneuron target to consider for moderation of motoneuron excitability in addition to 5HT receptors (Murray et al 2010). If SK channels in somatic and dendritic locations differ only by the source of calcium that activates them, their manipulation would affect I-f gains as well as PIC activation and deactivation.…”

Section: Mechanisms Underlying Pic Dysregulation After Scimentioning

confidence: 66%

“…A primary factor is the emergence of constitutive activity of 5HT 2B and 2C receptors producing recovery of PIC expression and independence of normal neuromodulatory control of PICs (Murray et al 2010(Murray et al , 2011. Given this state of chronic PIC facilitation, mechanisms that activate or suppress activation of PICs are potentially important factors in causing or reducing motoneuron hyperexcitability.…”

Section: Mechanisms Underlying Pic Dysregulation After Scimentioning

confidence: 99%

Differential contributions of somatic and dendritic calcium-dependent potassium currents to the control of motoneuron excitability following spinal cord injury

2012

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The hyperexcitability of alpha-motoneurons and accompanying spasticity following spinal cord injury (SCI) have been attributed to enhanced persistent inward currents (PICs), including L-type calcium and persistent sodium currents. Factors controlling PICs may offer new therapies for managing spasticity. Such factors include calcium-activated potassium (KCa) currents, comprising in motoneurons an after-hyperpolarization-producing current (I KCaN ) activated by N/P-type calcium currents, and a second current (I KCaL ) activated by L-type calcium currents (Li and Bennett in J neurophysiol 97:767-783, 2007). We hypothesize that these two currents offer differential control of PICs and motoneuron excitability based on their probable somatic and dendritic locations, respectively. We reproduced SCI-induced PIC enhancement in a two-compartment motoneuron model that resulted in persistent dendritic plateau potentials. Removing dendritic I KCaL eliminated primary frequency range discharge and produced an abrupt transition into tertiary range firing without significant changes in the overall frequency gain. However, I KCaN removal mainly increased the gain. Steady-state analyses of dendritic membrane potential showed that I KCaL limits plateau potential magnitude and strongly modulates the somatic injected current thresholds for plateau onset and offset. In contrast, I KCaN had no effect on the plateau magnitude and thresholds. These results suggest that impaired function of I KCaL may be an important intrinsic mechanism underlying PIC-induced motoneuron hyperexcitability following SCI.

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“…In previous articles, we examined how spasms can be controlled by reducing PICs (Murray et al 2010(Murray et al , 2011. The present article examines how we can control spasms by reducing EPSPs by replacing lost 5-HT innervation with 5-HT 1 receptor agonists.…”

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confidence: 96%

Polysynaptic excitatory postsynaptic potentials that trigger spasms after spinal cord injury in rats are inhibited by 5-HT_1B and 5-HT_1F receptors

Murray

Stephens

Rank

et al. 2011

Journal of Neurophysiology

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DJ. Polysynaptic excitatory postsynaptic potentials that trigger spasms after spinal cord injury in rats are inhibited by 5-HT 1B and 5-HT 1F receptors. J Neurophysiol 106: 925-943, 2011. First published June 8, 2011 doi:10.1152/jn.01011.2010.-Sensory afferent transmission and associated spinal reflexes are normally inhibited by serotonin (5-HT) derived from the brain stem. Spinal cord injury (SCI) that eliminates this 5-HT innervation leads to a disinhibition of sensory transmission and a consequent emergence of unusually long polysynaptic excitatory postsynaptic potentials (EPSPs) in motoneurons. These EPSPs play a critical role in triggering long polysynaptic reflexes (LPRs) that initiate muscles spasms. In the present study we examined which 5-HT receptors modulate the EPSPs and whether these receptors adapt to a loss of 5-HT after chronic spinal transection in rats. The EPSPs and associated LPRs recorded in vitro in spinal cords from chronic spinal rats were consistently inhibited by 5-HT 1B or 5-HT 1F receptor agonists, including zolmitriptan (5-HT 1B/1D/1F ) and LY344864 (5-HT 1F ), with a sigmoidal dose-response relation, from which we computed the 50% inhibition (EC 50 ) and potency (Ϫlog EC 50 ). The potencies of 5-HT receptor agonists were highly correlated with their binding affinity to 5-HT 1B and 5-HT 1F receptors, and not to other 5-HT receptors. Zolmitriptan also inhibited the LPRs and general muscle spasms recorded in vivo in the awake chronic spinal rat. The 5-HT 1B receptor antagonists SB216641 and GR127935 and the inverse agonist SB224289 reduced the inhibition of LPRs by 5-HT 1B agonists (zolmitriptan). However, when applied alone, SB224289, SB216641, and GR127935 had no effect on the LPRs, indicating that 5-HT 1B receptors do not adapt to chronic injury, remaining silent, without constitutive activity. The reduction in EPSPs with zolmitriptan unmasked a large glycine-mediated inhibitory postsynaptic current (IPSC) after SCI. This IPSC and associated chloride current reversed at Ϫ73 mV, slightly below the resting membrane potential. Zolmitriptan did not change motoneuron properties. Our results demonstrate that 5-HT 1B/1F agonists, such as zolmitriptan, can restore inhibition of sensory transmission after SCI without affecting general motoneuron function and thus may serve as a novel class of antispastic drugs. serotonin; muscle spasms; spasticity; motoneurons; synaptic input; triptans DESCENDING BRAIN STEM SYSTEMS innervating the spinal cord, especially those releasing serotonin (5-HT) and norepinephrine (NE), potently inhibit sensory transmission to spinal motoneurons and ascending tracts, ultimately attenuating both segmental reflexes and sensory perception (reviewed by Lundberg 1982;Millan 2002;Schmidt and Jordan 2000;Yoshimura and Furue 2006). Both 5-HT and NE directly inhibit sensory transmission by activating inhibitory G i protein-coupled receptors, such as 5-HT 1A , 5-HT 1B , 5-HT 1D , and ␣ 2 -adrenergic receptors, on sensory afferent terminals (including low-threshold group I an...

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Motoneuron Excitability and Muscle Spasms Are Regulated by 5-HT_2Band 5-HT_2CReceptor Activity

Cited by 126 publications

References 96 publications

Activation of 5-HT2A receptors upregulates the function of the neuronal K-Cl cotransporter KCC2

Activation of 5-HT2A receptors upregulates the function of the neuronal K-Cl cotransporter KCC2

Differential contributions of somatic and dendritic calcium-dependent potassium currents to the control of motoneuron excitability following spinal cord injury

Polysynaptic excitatory postsynaptic potentials that trigger spasms after spinal cord injury in rats are inhibited by 5-HT_1B and 5-HT_1F receptors

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Motoneuron Excitability and Muscle Spasms Are Regulated by 5-HT2Band 5-HT2CReceptor Activity

Cited by 126 publications

References 96 publications

Activation of 5-HT2A receptors upregulates the function of the neuronal K-Cl cotransporter KCC2

Activation of 5-HT2A receptors upregulates the function of the neuronal K-Cl cotransporter KCC2

Differential contributions of somatic and dendritic calcium-dependent potassium currents to the control of motoneuron excitability following spinal cord injury

Polysynaptic excitatory postsynaptic potentials that trigger spasms after spinal cord injury in rats are inhibited by 5-HT1B and 5-HT1F receptors

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Motoneuron Excitability and Muscle Spasms Are Regulated by 5-HT_2Band 5-HT_2CReceptor Activity

Polysynaptic excitatory postsynaptic potentials that trigger spasms after spinal cord injury in rats are inhibited by 5-HT_1B and 5-HT_1F receptors