Hanno Fischer

Fast inhibitory synapses: targets for neuromodulation and development of vertebrate motor behaviour

Locomotor networks must possess the inherent flexibility to adapt their output. In this review we discuss evidence from a simple vertebrate locomotor network that suggests fast inhibitory synapses are important targets for the forms of neuromodulation that afford this flexibility. Two important inhibitory transmitters, glycine and GABA, are present in the CNS of Xenopus tadpoles, where they each play distinct roles in the control of swimming. Glycine, but not GABA, contributes to the inhibitory mid-cycle component of each swim-cycle, the strength of which determines the frequency of swimming. Meanwhile, GABA release onto the swim network prematurely terminates swimming episodes. Hence, glycine controls how fast, whilst GABA controls how far the tadpole swims. Our work has focused on how the amines serotonin (5-HT) and noradrenaline (NA), and more recently the gas nitric oxide (NO), selectively target glycine and GABA release in the spinal cord to modulate swimming. In particular, we have identified three brainstem populations of nitrergic neurons, which suggests that nitric oxide may co-localise with 5-HT, NA and GABA. Here we review this work and suggest a hierarchy of brainstem modulatory systems, with NO acting as a metamodulator.

Adrenoreceptor-mediated modulation of the spinal locomotor pattern during swimming in Xenopus laevis tadpoles

This study focused on the contribution of different adrenoreceptor subtypes to the modulation of fictive swimming activity in a relatively simple, yet intact, lower vertebrate system, the immobilized Xenopus laevis tadpole and explored their possible role in mediating the noradrenergic modulation of spinal motor networks. In Xenopus embryos, near the time of hatching, activation of α1 adrenoreceptors increased the duration of episodes of fictive swimming, whilst in larvae, 24 h after hatching, they were decreased. Activation of α2 adrenoreceptors, however, markedly reduced episode duration at both developmental stages. Cycle periods in both stages were increased by the activation of α1 and/or α2 receptor subclasses, whereas β adrenoreceptors were not apparently involved in the modulation of cycle periods or the duration of swim episodes. However, both β and α1 receptor activation decreased the intersegmental delay in the head‐to‐tail propagation of swimming activity, while α2 receptors did not influence these rostro‐caudal delays. Activation of neither α, nor β, receptor subclasses had any consistent effect on the duration of ventral motor bursts. Our findings suggest that noradrenergic modulation of the swim‐pattern generator in Xenopus tadpoles is mediated through the activation of α and β adrenoreceptors. In addition, activation of particular receptor subclasses might enable the selective modulation of either the segmental rhythm generating networks, the intersegmental coordination of those networks or control at both levels simultaneously.

Alpha-adrenoreceptor activation modulates swimming via glycinergic and GABAergic inhibitory pathways in Xenopus laevis tadpoles

This study focuses upon the network pathways underlying the adrenoreceptor‐mediated modulation of fictive swimming in the immobilized Xenopus laevis tadpole. As shown recently, noradrenaline (NA) increases cycle periods while simultaneously reducing the rostrocaudal delay in head‐to‐tail firing and the duration of swimming episodes. Furthermore, both swimming frequency and duration are reduced by selective pharmacological activation of α1‐ and/or α2‐adrenoreceptors, while α1‐receptor activation also reduces rostrocaudal delays. We show that NA could still modulate aspects of swimming after blocking either glycine or GABAA receptors with strychnine and bicuculline, respectively. Furthermore, after prior application of NA, strychnine could counteract noradrenergic effects on cycle periods and rostrocaudal delays, while bicuculline could counteract effects on cycle periods, suggesting that these two fast inhibitory pathways are both involved in the NA modulation of swimming. In addition, blocking glycine receptors reduced the effects of α1‐receptors on cycle periods and delays, while blocking GABAA receptors had no effect. Blocking either glycine or GABAA receptors, however, lessened the reduction in swimming frequency by α2‐receptors. In addition, pre‐application of bicuculline prevented a reduction in episode durations by NA, α1‐ and α2‐receptors. Our findings suggest that the noradrenergic modulation of Xenopus swimming is mediated via α‐adrenoreceptors interacting with both glycinergic and GABAergic inhibitory pathways. Both α1‐ and α2‐receptor activation influences the GABAergic pathway controlling the duration of swimming episodes and is involved in the glycinergic modulation of the swimming rhythm and its longitudinal co‐ordination, with α2‐receptors additionally affecting swimming frequency through GABAergic pathways.