Dopaminergic and serotonergic modulation of cellular and locomotor network properties in the lamprey spinal cord

Sammanfattning: Motor activity is the basis for all behavior. It is therefore important to study the processes generating movement such as the neuronal networks in the spinal cord that generates and controls locomotion. The lamprey is used as a model system for the study of locomotion. Although, the lamprey is a simple vertebrate., it retains the same overall organization of the central nervous system (CNS) as higher vertebrates which makes it possible to, at least to some extent, extrapolate results to higher animals. In the intact animal, the spinal central pattern generator (CPG) for locomotion is activated by glutamatergic input from reticulospinal axons. Fictive swimming can be induced in the in vitro preparation of the isolated spinal cord through application of excitatory amino acids such as N-methyl-D-aspartate (NMDA). 5-Hydroxytryptamine (5-HT, serotonin) and dopamine (DA) are co-localized and presumably co-released in a ventromedial plexus that extends along the full length of the spinal cord. Descending 5-HT-ir fibers are also present in the dorsal and lateral areas. Both transmitters are important modulatory neurotransmitters of the locomotor central pattern generator in the lamprey spinal cord and largely act in a synergistic way. 5-HT as well as DA at high concentration depress the frequency of NMDA-induced fictive swimming and increases the intensity of ventral root bursts. In contrast, DA at low frequency increases the burst frequency. Both transmitters depresses glutamatergic synaptic transmission from reticulospinal axons to gray matter neurons via presynaptic mechanisms. 5-HT but not DA also modulates sensory synaptic transmission, DA on the other hand modulates both excitatory, and inhibitory glycinergic intra-spinal synaptic transmission. DA and 5-HT both reduce the late afterhyperpolarization (AHP) following the action potential and thereby depresses spike frequency adaptation. While 5-HT via the activation of 5-HT1A-like receptors reduces the late AHP through a direct action on the underlying apaminsensitive Ca2+-dependent K+ channels (KCa), DA through activation of D2 receptors depresses the N-type Ca2+ current during the action potential and thereby reduces the activation of KC2 channels. The pharmacology of the serotonergic modulation of fictive swimming is equivalent to that of the depression of the late AHP. This together with previous simulation studies indicates that the depression of the late AHP is a mechanism involved in the effects observed on the CPG operation. In contrast the 5-HT receptor responsible for the depression of sensory synaptic transmission is of another type. Pharmacological classification of the dopaminergic modulation of synaptic transmission differs from that of the depression of the late AHP which indicates that at least two DA receptors are present in the lamprey spinal cord. Intrinsic rhythmic membrane potential depolarizations occur in many neuronal cell types in the lamprey spinal cord and have been suggested to contribute to the generation of locomotion primarily at low frequencies. These oscillations are due to the voltage-dependent Mg2+ block of NMDA receptor channels. The oscillations are to a large extent controlled by an interaction between Ca2+ influx through voltage-sensitive channels and NMDA-receptor channels and KCa channels. 5-HT as well as DA modulates the oscillations. While 5-HT increases the duration of the depolarized phase, DA instead depresses the depolarized plateau duration. High-voltage activated (HVA) Ca2+ currents are activated during but appears not to be necessary for the generation of oscillations. Similar processes to those studied here are modulated and controlled by 5-HT in many species such as the neonatal rat, Xenopus tadpole and the turtle. The effects on cellular and locomotor network properties in lamprey are similar to those observed in other vertebrates. Furthermore DA and 5-HT appears to have similar and complementary effects on many processes.