Serotonin patterns locomotor network activity in the developing zebrafish by modulating quiescent periods

Abstract

Developing neural networks follow common trends such as expression of spontaneous, recurring activity patterns, and appearance of neuromodulation. How these processes integrate to yield mature, behaviorally relevant activity patterns is largely unknown. We examined the integration of serotonergic neuromodulation and its role in the functional organization of the accessible locomotor network in developing zebrafish at behavioral and cellular levels. Locally restricted populations of serotonergic neurons and their projections appeared in the hindbrain and spinal cord of larvae after hatching (approximately day 2). However, 5-HT affected the swimming pattern only from day 4 on, when sustained spontaneous swimming appeared. 5-HT and its agonist quipazine increased motor output by reducing intervals of inactivity, observed behaviorally (by high-speed video) and in recordings from spinal neurons during fictive swimming (by whole-cell current clamp). 5-HT and quipazine had little effect on the properties of the activity periods, such as the duration of swim episodes and swim frequency. Further, neuronal input resistance, rheobasic current, and resting potential were not affected significantly. The 5-HT antagonists methysergide and ketanserin decreased motor output by prolonging the periods of inactivity with little effect on the active swim episode or neuronal properties. Our results suggest that 5-HT neuromodulation is integrated early in development of the locomotor network to increase its output by reducing periods of inactivity with little effect on the activity periods, which in contrast are the main targets of 5-HT neuromodulation in neonatal and adult preparations.

Serotoninergic Modulation of Chloride Homeostasis during Maturation of the Locomotor Network in Zebrafish

“…Surprisingly, this occurs without affecting the properties of active (swim) episodes, which retain a normal presynaptic drive. This excludes the mechanisms described in other and more mature preparations in which presynaptic modulation and postsynaptic changes in conductance occur (for review, see Schmidt and Jordan, 2000;Brustein et al, 2003b). In contrast to the lack of effects of 5HT on the active (swim) period, 5-HT reduced intervals of quiescence, whereas its antagonists prolonged them considerably (Brustein et al, 2003b), a pattern reminiscent of that described in other highly excitable developing neuronal networks (O'Donovan, 1999;Ben-Ari, 2001;Zhang and Poo, 2001).…”

“…This excludes the mechanisms described in other and more mature preparations in which presynaptic modulation and postsynaptic changes in conductance occur (for review, see Schmidt and Jordan, 2000;Brustein et al, 2003b). In contrast to the lack of effects of 5HT on the active (swim) period, 5-HT reduced intervals of quiescence, whereas its antagonists prolonged them considerably (Brustein et al, 2003b), a pattern reminiscent of that described in other highly excitable developing neuronal networks (O'Donovan, 1999;Ben-Ari, 2001;Zhang and Poo, 2001). These effects of 5HT and its antagonists on the duration of the quiescent intervals were not accompanied by apparent changes in membrane properties, excluding ionic conductances as the major targets for 5HT modulation during quiescent intervals (Brustein et al, 2003b).…”

“…We showed previously that endogenous serotonin (5HT) modulates the activity state of the neuronal network underlying locomotion in the developing zebrafish by modulating the duration of quiescent intervals that interrupt activity periods (Brustein et al, 2003b). Surprisingly, this occurs without affecting the properties of active (swim) episodes, which retain a normal presynaptic drive.…”

Neurogenic Role of the Depolarizing Chloride Gradient Revealed by Global Overexpression of KCC2 from the Onset of Development

“…Considering that the embryos were intact and embedded in agarose, we assume that the final drug concentrations were 10 times lower (Brustein et al, 2003;Brustein and Drapeau, 2005).…”

Loss of Flight and Associated Neuronal Rhythmicity in Inositol 1,4,5-Trisphosphate Receptor Mutants ofDrosophila

“…In Drosophila, inhibition of serotonin synthesis has been shown to cause excessive branching of serotonergic axon terminals during embryonic and larval development (Budnik et al, 1989). More recently, serotonin has been shown to affect development of the swimming circuit in zebrafish (Brustein et al, 2003), and a role for serotonergic interneurons has been described during development of the left-right coordination of rhythmic motor activity in rat spinal cord (Nakayama et al, 2002). Together with these studies, it is reasonable to postulate that itpr mutants affect development of the flight circuit through modulating serotonin release.…”