The Journal of Neurophysiology Vol. 79 No. 5 May 1998, pp. 2804-2808
Copyright ©1998 by the American Physiological Society

RAPID COMMUNICATION

NMDA Receptor-Mediated Oscillatory Activity in the Neonatal Rat Spinal Cord Is Serotonin Dependent

Jason N. Maclean, Kristine C. Cowley, and Brian J. Schmidt

Department of Physiology, University of Manitoba, Winnipeg, Manitoba R3E 0W3, Canada

	ABSTRACT

Abstract Introduction Methods Results Discussion References

MacLean, Jason N., Kristine C. Cowley, and Brian J. Schmidt. NMDA receptor-mediated oscillatory activity in the neonatal rat spinal cord is serotonin dependent. J. Neurophysiol. 79: 2804-2808, 1998. The effect of serotonin (5-HT) receptor blockade on rhythmic network activity and on N-methyl-D-aspartate (NMDA) receptor-induced membrane voltage oscillations was examined using an in vitro neonatal rat spinal cord preparation. Pharmacologically induced rhythmic hindlimb activity, monitored via flexor and extensor electroneurograms or ventral root recordings, was abolished by 5-HT receptor antagonists. Intrinsic motoneuronal voltage oscillations, induced by NMDA in the presence of tetrodotoxin (TTX), either were abolished completely or transformed to long-lasting voltage shifts by 5-HT receptor antagonists. Conversely, 5-HT application facilitated the expression of NMDA-receptor-mediated rhythmic voltage oscillations. The results suggest that an interplay between 5-HT and NMDA receptor actions may be critical for the production of rhythmic motor behavior in the mammalian spinal cord, both at the network and single cell level.

	INTRODUCTION

Abstract Introduction Methods Results Discussion References

Rhythmic motor activity, including locomotion, can be induced in the in vitro neonatal rat spinal cord by bath application of a variety of neurochemicals, such as N-methyl-D-aspartate (NMDA) or serotonin (5-HT) (Cazalets et al. 1992; Smith et al. 1988). The combined administration of NMDA and 5-HT may be more effective than either substance alone in promoting locomotor-like activity (Sqalli-Houssaini et al. 1993). However, elicitation of neural activity in response to whole-cord application of an excitatory substance does not prove that activation of the corresponding receptor system is critical for the production of the same behavior in the intact animal. Instead, the use of selective antagonists can help clarify which endogenous receptor types are important. For instance, both NMDA and non-NMDA excitatory amino acid (EAA) receptor antagonists suppress rhythmic motor activity induced by bath-applied EAAs (Cazalets et al. 1992; Smith et al. 1988). In addition, EAA receptor antagonists suppress spinal motor rhythms induced by non-EAA neurochemical activators and brain stem electrical stimulation (Beato et al. 1997; Schmidt et al. 1989; Smith et al. 1988). These observations suggest a role for endogenous NMDA and non-NMDA EAA receptors in the generation of rhythmic motor activity in the mammalian spinal cord. NMDA receptor activation is of particular interest because it elicits inherent oscillations of membrane potential in rat spinal interneurons and motoneurons (Hochman et al. 1994a,b), a property that may be well suited for the production of rhythmic behaviors such as locomotion.

Although administration of 5-HT receptor antagonists to spinal cats reverses perturbations of the locomotor pattern produced by 5-HT agonists (Barbeau and Rossignol 1990), it remains to be shown whether endogenous 5-HT receptor activation is critical for network rhythmogenesis in the mammalian spinal cord. In the lamprey, application of 5-HT decreases swimming frequency (Harris-Warrick and Cohen 1985) and slows the repolarizing phase of NMDA receptor-mediated intrinsic voltage oscillations in spinal neurons (Wallen et al. 1989). In contrast, 5-HT is required for the maturation of locomotor rhythms (Sillar et al. 1995) and the expression of intrinsic voltage oscillations (Scrymgeour-Wedderburn et al. 1997; Sillar and Simmers 1994) in amphibian spinal neurons. The present study examines whether 5-HT is essential for network rhythmogenesis and/or modulation of NMDA-mediated oscillatory activity in the mammalian spinal cord.

Some of the following data has been presented previously in abstract form (MacLean and Schmidt 1995; MacLean et al. 1996).

	METHODS

Abstract Introduction Methods Results Discussion References

Experiments were performed on 37 Sprague-Dawley rats (aged 2-7 days). Techniques for isolation of the spinal cord, extracellular recording, and neurochemical induction of rhythmic activity have been described previously (e.g., Cowley and Schmidt 1995). In brief, animals were anesthetized with ether, decapitated, eviscerated, and placed in a bath chamber containing (in mM) 128 NaCl, 3.0 KCl, 0.5 Na₂H₂PO₄, 1.5 CaCl₂, 1.0 MgSO₄, 21 NaHCO₃, and 30 glucose equilibrated to pH 7.4 with 95% O₂-5% CO₂. Bilaterally intact spinal cords, transected at C1, then were isolated. In some experiments, rhythmic network activity in the spinal cord was monitored via electroneurogram (ENG) recordings of ankle flexor(peroneal) and extensor (tibial) nerves or bilateral L₂ and L₅ ventral root recordings. In other experiments, the activity of synaptically isolated motoneurons in tetrodotoxin (TTX) was monitored with whole cell patch recordings.

Whole cell recordings of motoneurons were obtained as previously described (Hochman et al. 1994b). Recording pipettes contained (in mM) 140 K-gluconate, 11 ethylene glycol-bis(-aminoethyl ether) N,N,N',N',-tetraacetic acid, 35 KOH, 10 N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid, and 1 CaCl₂. Cells were approached through a pial patch made over the ventrolateral surface of the spinal cord and were identified as motoneurons by their antidromic response to ventral root stimulation. The recordings were obtained with an Axopatch 1D amplifier (Axon Instruments), filtered at 2 kHz. Series resistance was monitored continuously and compensated. The electrode-bath solution liquid junction potential (10 mV) was corrected for all data presented. Data was acquired and analyzed on a 486-based computer using pClamp software (v6.0 Axon instruments). Records also were analyzed using special purpose software on a Masscomp 5400 computer.

	RESULTS

Abstract Introduction Methods Results Discussion References

We first examined the effects of 5-HT receptor blockade on neurochemically induced network rhythmogenesis. Hindlimb rhythmic activity was induced by NMDA (6-10 µM, n = 11), acetylcholine (ACh, 60 µM) in combination with edrophonium (EDRO, 200 µM, n = 1) or NMDA (6-16 µM) and ACh/EDRO (60/200 µM) combined (n = 2). Note that nonlocomotor-like patterns of rhythmic activity, as for example the coactivation of flexor and extensor ENGs shown in Fig. 1A, are not uncommon using NMDA alone and/or ACh in this preparation (Cowley and Schmidt 1994).

View larger version (19K): [in this window] [in a new window]   FIG. 1. Serotonin (5-HT) receptor antagonists abolished network rhythmic activity. A: peroneal (Per) and tibial (Tib) rhythmic activity was induced by N-methyl-D-aspartate (NMDA, Ai) and abolished by methysergide (160 µM, Aii). B: rhythmic activity induced by NMDA (Bi) was blocked by a low concentration of mianserin (1 µM, Bii).

In 11/11 preparations, rhythmic activity was abolished after the bath application of 5-HT receptor antagonists (methysergide, 20-100 µM, n = 3, Fig. 1A; mianserin, 70-200 µM, n = 6; or cyproheptadine, 60-80 µM, n = 2). In 3 of 3 preparations, low concentrations of mianserin (1 µM) or ketanserin (2µM) were also effective in terminating NMDA-induced rhythmic activity (Fig. 1B), although the latency to full blockade was longer (>60 min) than that required (15-30 min) using higher concentrations of the 5-HT antagonists. In three other experiments, NMDA was used to induce rhythmic activity, after which it was washed out of the bath. These cords then were exposed to low concentrations of mianserin (1 µM) for 90 min before reapplication of NMDA in graded concentrations from 2 to 20 µM. Preincubation with mianserin prevented the elicitation of rhythmic activity.

Among the remaining 20 preparations, 20 motoneurons were examined using whole cell recordings. Seventeen of these motoneurons were studied in the presence of NMDA (2-20 µM) and synaptic isolation with TTX (1.5 µM). Three types of motoneuron membrane behavior were observed. Some motoneurons (n = 3) developed regular oscillations, characterized by peak depolarizations that were shorter in duration than the rise or falling phases of the voltage fluctuation (Fig. 2Ai). The mean values for amplitude, frequency, and duration of these oscillations were20.4 ± 9.2 (SD) mV, 0.7 ± 0.2 Hz, and 427 ± 23 ms, respectively. The second type of NMDA-induced behavior featured recurrent but long-lasting shifts in membrane voltage (n = 5, Fig. 2Aii). The duration of the depolarized phase in these cells averaged 3.2 ± 2.0 s, and the mean amplitude was similar to the amplitude of oscillations (21.6 ± 1.8 mV). The voltage shifts were rhythmic in three of the five motoneurons (mean frequency 0.26 ± 0.03 Hz) and arrhythmic in the other two cells. The third type of response consisted of sustained depolarization (10.8 ± 2.4 mV, n=9; Fig. 2Bii).

View larger version (52K): [in this window] [in a new window]   FIG. 2. 5-HT modulation of tetrodotoxin (TTX)-resistant NMDA-induced voltage oscillations. Ai: mianserin (120 µM) transformed NMDA-induced rhythmic oscillations to long-lasting shifts of membrane voltage. Aii: 5-HT (50 µM) transformed long-lasting voltage shifts produced by NMDA alone into rhythmic oscillations. Time elapsed after the addition of mianserin (Ai) and 5-HT (Aii) is indicated. Bi: oscillations induced by NMDA and 5-HT were abolished by ketanserin (100 µM). Bii: NMDA-induced stable membrane depolarization, which was transformed subsequently to rhythmic voltage oscillations by 5-HT (30 µM). C: in the absence of 5-HT receptor blockade, oscillations persisted despite manipulation of the holding potential, although amplitude varied in relation to the holding potential. D: in the absence of 5-HT receptor blockade, TTX-resistant NMDA-mediated oscillations were well maintained for >60 min. Records shown in Aii and Bi are from the same motoneuron.

The effect of the 5-HT receptor antagonist mianserin (100-150 µM, n = 7) or ketanserin (100 µM, n = 1) on TTX-resistant oscillations induced by NMDA alone (2.5-4.5 µM, n = 3) or by NMDA and 5-HT (15-100 µM) combined (n = 5) was examined. Oscillations induced by NMDA and 5-HT were completely abolished in three motoneurons (e.g., Fig. 2Bi). In five motoneurons, exposed to either NMDA alone (n = 3) or both NMDA and 5-HT(n = 2), oscillations and were transformed into long-lasting recurrent voltage shifts (Fig. 2Ai). The voltage shifts were arrhythmic in four of five cells. Their amplitude (20.9 ± 5.9 mV) and duration (2.2 ± 0.8 s) were similar to the values obtained for long-lasting voltage shifts induced by NMDA alone. The emergence of fully developed long-lasting voltage shifts required up to 30 min or longer (e.g., Fig. 2Ai) after adding the 5-HT receptor antagonist and was accompanied by gradual membrane hyperpolarization. This transformation was not simply due to membrane hyperpolarization because hyperpolarizing current injection alone, in the absence of a 5-HT antagonist, failed to convert oscillations into long-lasting voltage shifts (Fig. 2C). In the absence of 5-HT antagonists, oscillations persisted for >1 h in those neurons that initially displayed oscillatory activity (n = 8, e.g., Fig. 2D), suggesting that the development of long-lasting voltage shifts was unrelated to progressive dialysis of intracellular contents with the pipette filling solution or "run-down."

The effect of adding 5-HT (15-100 µM) was examined in motoneurons displaying long-lasting membrane voltage shifts (n = 3) or tonic depolarization (n = 9) in response to NMDA alone. Seven of these motoneurons (3 with long-lasting voltage shifts and 4 with tonic depolarization) developed oscillations in response to 5-HT (Fig. 2, Aii and Bii, respectively). The mean amplitude, frequency, and duration of these 5-HT facilitated oscillations were 11.8 ± 4.5 mV, 0.7 ± 0.3 Hz, and 755 ± 474 ms, respectively. The transformation between long-lasting voltage shifts and oscillations always occurred as a slow transition rather than an abrupt threshold-like event (Fig. 2A). Five of the nine motoneurons that initially displayed tonic depolarization in response to NMDA failed to develop oscillations after 5-HT was added; the input resistance, time constant, resting membrane potential, and spike height of these motoneurons were 60.3 ± 49.9 M, 13.9 ± 9.7 ms, -76.6 ± 7.2 mV, and 91.0 ± 10.1 mV, respectively. The corresponding values for motoneurons that were capable of developing oscillations (n = 13) were 95.0 ± 57.0 M, 22.5 ± 12.5 ms, -74.1 ± 5.8 mV, and 68.1 ± 22.1 mV (n = 13). Comparing the two groups, no significant difference in the mean values of these membrane properties was found (Student's t-test, P >0.1).

	DISCUSSION

Abstract Introduction Methods Results Discussion References

Numerous studies have documented that 5-HT influences the excitability of motoneurons (e.g., Barasi and Roberts 1974; Elliot and Wallis 1992; Takahashi and Berger 1990; White and Neuman 1980; Ziskind-Conhaim et al. 1993) and facilitates the development of plateau potentials (Hounsgaard and Kiehn 1989; Hounsgaard et al. 1988). Colocalization of glutamate and 5-HT in synaptic boutons surrounding motoneuron cell bodies (Nicholas et al. 1992) also suggests that EAA and 5-HT receptor systems may closely interact. 5-HT depresses NMDA receptor-mediated responses in the locus coeruleus (Charlety et al. 1993), dorsal horn (Murase et al 1990), and ventral horn (Chesnoy-Marchais and Barthe 1996) of the spinal cord. In contrast, 5-HT enhances the effects of NMDA application on neocortical cells (Nedergaard et al. 1986, 1987; Rahman and Neuman 1993; Reynolds et al. 1988), including the development of rhythmic bursting and TTX-resistant "depolarization shifts" (Nedergaard et al. 1986, 1987). A preliminary report indicated that similar 5-HT modulatory actions may be present in cat motoneurons (Flatman and Engberg 1990). Certainly the present results are compatible with an important role for5-HT in the control of rhythmic motor output in the mammalian spinal cord, both at the single cell and network level.

In the presence of TTX, most motoneurons failed to display oscillations in response to NMDA alone, consistent with a requirement for 5-HT receptor-mediated facilitation of intrinsic oscillatory activity. The few TTX-treated motoneurons (3 of 17) that did develop oscillations after adding NMDA alone may have been under the influence of residual 5-HT receptor activation despite TTX. This possibility is supported by the observation that subsequent addition of5-HT antagonists transformed oscillations in these cells into long-lasting voltage shifts.

In the absence of TTX, 5-HT antagonists always abolished rhythmic network activity. Thus it appears that endogenous 5-HT receptor activation must persist, at least to some degree, in the isolated spinal cord, despite removal of the brain stem, and thus the source of spinal 5-HT (Dahlstrom and Fuxe 1965; although, see Newton and Hamill 1988).

Activation of either 5-HT_1A or 5-HT₂ receptors can modulate NMDA receptor-mediated currents via second-messenger systems (Blank et al. 1996; Chen and Huang 1992). A recent study of embryonic and larval Xenopus spinal cord neurons suggests that 5-HT_1A receptor activation facilitates the voltage-dependent blockade of NMDA channels by Mg²⁺; and this interaction may explain why NMDA and5-HT receptor coactivation is required for the production of voltage oscillations in these cells (Scrymgeour-Wedderburn et al. 1997). In contrast, our observations, using mianserin and ketanserin, suggest that NMDA-induced oscillations in the neonatal rat spinal motoneurons may depend on 5-HT₂ receptor activation. However, confirmation of the specific receptor type(s) awaits further investigation. It is also possible that the interaction between 5-HT and NMDA in the production of motoneuronal oscillations may occur via 5-HT effects that are independent of direct modulation of NMDA receptors or that 5-HT may act as an open channel voltage-dependent blocker of the NMDA ionophore (Chesnoy-Marchais and Barthe 1996) independent of 5-HT receptor activation.

5-HT and other neuromodulators have a critical role in functionally reconfiguring invertebrate rhythmogenic circuits; in these systems, modulators regulate the strength of synaptic interactions and intrinsic membrane properties of neuronal elements distributed throughout the network (e.g., Johnson et al. 1995; Katz et al. 1994). Although the present study demonstrates 5-HT receptor-mediated modulation of intrinsic membrane properties in motoneurons, it remains to be shown whether similar modulation occurs in other neural components of the network. It is quite possible that the blockade of rhythmogenic activity by 5-HT antagonists was related, at least in part, to the actions of the antagonists on network interneurons. Regardless of the specific sites of action, our results suggest that 5-HT is critical for the expression of rhythmic motor activity in the mammalian spinal cord.

	ACKNOWLEDGEMENTS

  We thank Dr. S. Hochman for helpful advice.

  This work was supported by the Health Sciences Centre Foundation, Winnipeg, Manitoba. J. N. MacLean was supported by a Manitoba Health Research Council studentship and the Rick Hansen Man-in-Motion Legacy Fund.

	FOOTNOTES

  Address for reprint requests: B. J. Schmidt, Dept. of Physiology, University of Manitoba, 770 Bannatyne Ave., Winnipeg, Manitoba R3E 0W3, Canada.

  Received 1 August 1997; accepted in final form 22 December 1997 .

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