Endogenous Monoamine Receptor Activation Is Essential for Enabling Persistent Sodium Currents and Repetitive Firing in Rat Spinal Motoneurons

Abstract

. Endogenous monoamine receptor activation is essential for enabling persistent sodium currents and repetitive firing in rat spinal motoneurons. J Neurophysiol 96: 1171-1186, 2006. First published June 7, 2006 doi:10.1152/jn.00341.2006. The spinal cord and spinal motoneurons are densely innervated by terminals of serotonin (5-HT) and norepinephrine (NE) neurons arising mostly from the brain stem, but also from intrinsic spinal neurons. Even after long-term spinal transection (chronic spinal), significant amounts (10%) of 5-HT and NE (monoamines) remain caudal to the injury. To determine the role of such endogenous monoamines, we blocked their action with monoamine receptor antagonists and measured changes in the sodium currents and firing in motoneurons. We focused on persistent sodium currents (Na PIC) and sodium spike properties because they are critical for enabling repetitive firing in motoneurons and are facilitated by monoamines. Intracellular recordings were made from motoneurons in the sacrocaudal spinal cord of normal and chronic spinal rats (2 mo postsacral transection) with the whole sacrocaudal cord acutely removed and maintained in vitro (cords from normal rats termed acute spinal). Acute and chronic spinal rats had TTX-sensitive Na PICs that were respectively 0.62 Ϯ 0.76 and 1.60 Ϯ 1.04 nA, with mean onset voltages of Ϫ63.0 Ϯ 5.6 and Ϫ64.1 Ϯ 5.4 mV, measured with slow voltage ramps. Application of 5-HT 2A , 5-HT 2C , and ␣1-NE receptor antagonists (ketanserin, RS 102221, and WB 4101, respectively) significantly reduced the Na PICs, and a combined application of these three monoamine antagonists completely eliminated the Na PIC, in both acute and chronic spinal rats. Likewise, reduction of presynaptic transmitter release (including 5-HT and NE) with long-term application of cadmium also eliminated the Na PIC. Associated with the elimination of the Na PIC in monoamine antagonists, the motoneurons lost their ability to fire during slow current ramps. At this point, the spike evoked by antidromic stimulation was not affected, suggesting that activation of the transient sodium current was not impaired. However, the spike evoked after a slow ramp depolarization was slightly reduced in height and rate-of-rise, suggesting decreased sodium channel availability as a result of increased channel inactivation. These results suggest that endogenous monoamine receptor activation is critical for enabling the Na PIC and decreasing sodium channel inactivation, ultimately enabling steady repetitive firing in both normal and chronic spinal rats.

Effects of the Noradrenergic System in Rat White Matter Exposed to Oxygen–Glucose DeprivationIn Vitro

“…Indeed, blocking ␣2Rs with the antagonist atipamezole drastically reduced ischemic Na ϩ rise, suggesting that the ␣2-signaling pathway is coupled to a major source of Na ϩ entry voltage-gated Na ϩ channels. The persistent Na ϩ channel is one route of Na ϩ influx during ischemia, and this persistent current was shown to be upregulated by monoamine receptors in rat spinal motoneurons (Harvey et al, 2006). Our findings are consistent with the notion that noradrenergic receptors in white matter axons can modulate persistent Na ϩ current during ischemia, thus leading to increased Na ϩ entry and secondarily to a greater Ca 2ϩ accumulation and more functional damage.…”

“…The effect could be directly axonal via ␣2 G-protein modulation of Na ϩ channels and AMPA receptors and/or through ␣2 receptors located on astrocytes. Previous studies indicate that adrenergic receptors exert potent modulatory actions on both TTX-sensitive Na ϩ channels [in particular on the persistent inward current mediated by these channels (Harvey et al, 2006)] and on AMPA receptors (Pralong and Magistretti, 1995), the two major putative Na ϩ entry pathways in damaged myelinated axons (Stys et al, 1993;Ouardouz et al, 2006) (Fig. 6).…”

Spasticity may defend skeletal muscle size and composition after incomplete spinal cord injury

“…This limitation, however, may be addressed by evidences that suggest that variability in motor neuron firing following acute SCI is small owing to loss of brain stem neuromodulators such as serotonin and norepinepherine that account for such variability. 45 Moreover, failure to document the exact dose of the anti-spastic medication administered to the HLI group might have underestimated the actual relationship between spasticity and muscle size by further inhibiting muscle tone. However, the administered dose was very minimal to influence the relationship especially if we considered the flaccid stage period.…”

The Whisking Rhythm Generator: A Novel Mammalian Network for the Generation of Movement

“…First discovered in cat spinal motoneurons (Schwindt and Crill 1980), these persistent inward currents (PICs) modulate the firing frequencies of motoneurons (Heckman et al 2003;Schwindt and Crill 1982). Thus by activating and amplifying PICs, 5-HT is reported to modulate firing in motoneurons (Harvey et al 2006b;Heckman et al 2005;Hounsgaard and Kiehn 1989;Hounsgaard et al 1988;Hsiao et al 1998). Here, we test the hypothesis that 5-HT is sufficient to generate rhythmic firing in vMNs through a graded facilitation of PICs.…”

“…In the intact animal, serotonergic drive to vMNs originates from a subset of serotonergic neurons in the brain stem that both project to vMNs in the lateral facial nucleus and receive projections from the vibrissa motor cortex (vMCx) Hattox et al 2002). Thus these serotonergic premotoneurons likely serve as the endogenous source of the 5-HT employed by vMNs to generate whisking rhythms.…”