Serotonin-Driven Long-Range Inhibitory Connections in the Cerebellar Cortex

Abstract

Disturbances of the serotoninergic neuromodulation in the cerebellar cortex have been involved in several types of ataxia, but the physiological action of serotonin in this structure remains poorly understood. We report that in slices of the rat cerebellar vermis, serotonin triggers the firing of an inhibitory interneuron presynaptic to Golgi cells. The Lugaro cell, a neglected interneuronal type, satisfies the expected criteria for this input, whereas basket cells, stellate cells, or Golgi cells do not. Lugaro cells are selectively excited by serotonin, and their firing behavior (sustained steady frequency in the 5-15 Hz range) resembles the pattern of occurrence of serotonin-evoked IPSCs in Golgi cells. Immunohistochemical stainings and single cell reconstructions show that Lugaro cell axons form a parasagittal plexus but also extend long transverse branches that run parallel to the parallel fibers and are partly myelinated. Electrophysiological data suggest that these transverse axons participate in synaptic contacts of the Lugaro cells with Golgi cells, and we calculated that in the intact cerebellum a given Lugaro cell contacts Ͼ100 Golgi cells. Serotonin modulation of Lugaro cells may constitute an intracortical switch involved in information patterning at the level of Golgi cells and granule cells populations, and particularly in synchronizations recorded along the transverse axis in vivo.

Besides Purkinje cells and granule neurons: an appraisal of the cell biology of the interneurons of the cerebellar cortex

“…They are found in all parts of the cerebellar cortex, where they are located at the border between the Purkinje cell layer and the upper part of the granule cell layer. Initial numerical estimates had put the Purkinje cell/ Lugaro cell ratio at about 15:1 in the rat (Dieudonne and Dumoulin 2000) and 30:1 in the cat (Sahin and HockWeld 1990). More recently, a detailed neurochemical analysis of large granule cell layer interneurons indicated that in the mouse, Lugaro cells account for about 1/3 of all inhibitory granule cell layer interneurons, and thus are more numerous than initially estimated (Simat et al 2007).…”

“…These dendrites are of rather variable length, measuring, in the rat, from some 100 to 700 m (Laine and Axelrad 1996). Lugaro cells are currently viewed as the primary target of serotoninergic input into the cerebellar cortex (Dieudonne and Dumoulin 2000). They are also innervated by recurrent Purkinje cell axon collaterals (Palay and Chan-Palay 1974), and basket cells (Fox et al 1967).…”

“…Indeed, there is a growing body of evidence that points to an intricate regulation of the sorting and membrane insertion of Glyt2, Gat-1, and Gat-2 (e.g., Muth et al 1998;Martinez-Maza et al 2001;Farhan et al 2008; see also Chiu et al 2002), which are expressed in large molecular layer interneurons of the cerebellum (cf the Allen Brain Atlas; Lein et al 2007). Intriguingly, Gat-2 is subject to regulation by serotonin; as mentioned above, Lugaro cells are the primary target of serotoninergic projections to the cerebellar cortex (Dieudonne and Dumoulin 2000).…”

Peripheral stimuli excite coronal beams of Golgi cells in rat cerebellar cortex

“…The precisely timed response components were generated in the model with trigeminal MF and PF excitation alone, i.e. without a need for other, non-modelled synaptic inputs to Golgi cells originating from Lugaro cells (Dieudonne ¤ and Dumoulin, 2000), stellate cells, climbing ¢bres, the pontine nuclei (Leergaard et al, 2000) or the lateral reticular nucleus.…”

“…Although other pathways and mechanisms cannot be excluded to have contributed to our experimental observations, it is unclear how they would generate delays with a spatially anisotropic pattern. For example, the inhibitory Lugaro cells were proposed to synchronise Golgi cells (Dieudonne ¤ and Dumoulin, 2000). It would indeed be di⁄cult to distinguish, from the CCH, common inhibition from common excitation as the cause of synchrony .…”