Why do serotonergic medications help some ataxias?
Serotonergic neuromodulation in the cerebellar cortex: cellular, synaptic, and molecular basis.
Abstract
The cerebellum, like most sensorimotor areas of the brain, receives a serotonergic innervation from neurons of the reticular formation. It is well established that local application of serotonin modulates the firing rate of cerebellar Purkinje cells in vivo and in vitro, but the mechanisms by which serotonin affects the cerebellar function are still poorly understood. Whereas interactions between serotonin, glutamate, and GABA have been reported to increase or decrease the firing frequency of Purkinje cells, there is little evidence for a modulation of excitatory and inhibitory synapses by serotonin in the cerebellar cortex.
Changes in the intrinsic electrical properties of Purkinje cells upon application of serotonin have also been reported, but their impact on Purkinje cell firing is unclear. The recent finding that serotonin specifically modulates the activity of Lugaro cells, a class of inhibitory interneurons of the cerebellar cortex, offers new insights on the action of this neuromodulator. The peculiar axonal projection and specific interneuronal targets of the Lugaro cells suggest that the action of serotonin might occur upstream of Purkinje cells through a resetting of the computational properties of the cerebellar cortex.
Understanding the mechanisms of the serotonergic modulation of the cerebellar cortex is of clinical relevance, as abnormal serotonin metabolism has been observed in animal models and pathological cases of motor disorders involving the cerebellum, and as chronic intravenous administration of L-5-hydroxytryptophan (5-HTP), a precursor of serotonin, was the first treatment shown to improve significantly cerebellar symptoms.
The cerebellar serotoninergic system and its possible involvement in cerebellar ataxia.
Abstract
A review concerning the characteristics of the cerebellar serotoninergic system is presented. In rat, cat and oppossum, the perikarya of origin are located in the brain stem raphe nuclei and in other brainstem structures. The projections to the cerebellar layers and deep nuclei include synaptic connections, but also non synaptic terminals, especially in a diffuse cortical plexus. Serotoninergic receptors have been described: 5-HT1B in the molecular layer and 5-HT2 in the inferior olive. Serotonin exerts neurophysiological effects on several target cells, directly or indirectly, presynaptically or postsynaptically. A modulatory effect on Purkinje cells is well documented. In thiamine deprived animals, a specific serotoninergic cerebellar syndrome includes a selective degeneration of the serotoninergic cerebellar system, an increase of the 5-HIAA cerebellar values and an exaggerated serotoninergic turnover. In human heredoataxias (Friedreich's ataxia and cerebellar cortical atrophy), serotoninergic disturbances have been observed in the CSF, including low 5-HIAA values and an increased serotoninergic turnover. Therapeutic results have been obtained with L-5-HTP, a precursor of serotonin, in several conditions presenting cerebellar ataxia. L-5-HTP resistance of olivopontocerebellar atrophies may be explained by the destruction of serotonin-sensitive target cells, especially Purkinje cells.
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