Serotonergic control of Purkinje cell maturation and climbing fibre elimination by 5‐HT₃ receptors in the juvenile mouse cerebellum

Abstract

Key points• Serotonin 3 (5-HT 3 ) receptors are expressed by excitatory granule cells in the cerebellum during early postnatal development.• Here we show a novel role for serotonin in the regulation of cerebellar postnatal development via 5-HT 3 receptors.• Using 5-HT 3A receptor knockout mice we show that 5-HT 3 receptors expressed by granule cells, via the glycoprotein reelin, regulate the morphological maturation of Purkinje cells.• The 5-HT 3A receptor knockout mice show abnormal physiological maturation of Purkinje cells and impaired short-term plasticity at the parallel fibre-Purkinje cell synapse, resulting in delayed climbing fibre elimination.• With these results, we provide a better understanding of the role of serotonin in the developing brain, the control it has on the postnatal maturation of the cerebellum, and the cerebellum as a highly adaptive system during early postnatal development.Abstract Functional serotonin 3 (5-HT 3 ) receptors are transiently expressed by cerebellar granule cells during early postnatal development, where they modulate short-term synaptic plasticity at the parallel fibre-Purkinje cell synapse. Here, we show that serotonin controls maturation of Purkinje cells in the mouse cerebellum. The 5-HT 3 receptors regulate morphological maturation of Purkinje cells during early postnatal development, and this effect is mediated by the glycoprotein reelin. Using whole-cell patch-clamp recordings we also investigated physiological development of Purkinje cells in 5-HT 3A receptor knockout mice during early postnatal development, and found abnormal physiological maturation, characterized by a more depolarized resting membrane potential, an increased input resistance and the ability to fire action potentials upon injection of a depolarizing current at an earlier age. Furthermore, short-term synaptic plasticity was impaired at both the parallel fibre-Purkinje cell and the climbing fibre-Purkinje cell synapses, and both the amplitude and the frequency of spontaneous miniature events recorded from Purkinje cells were increased. The expedited morphological and physiological maturation affects the whole cerebellar cortical network, as indicated by delayed climbing fibre elimination in 5-HT 3A receptor knockout mice. There was no difference between wild-type and 5-HT 3A receptor knockout mice in any of the morphological or physiological properties described above at later ages, indicating a specific time window during which serotonin regulates postnatal development of the cerebellum via 5-HT 3 receptors expressed by granule cells.

The serotonin 5-HT3 receptor: a novel neurodevelopmental target

“…First, ubiquitous post-/extra- and presynaptic expression of 5-HT 3 receptors was recently observed in glutamatergic granule cells of the cerebellum within the first three postnatal weeks in rodents (Oostland et al, 2011, 2013). 5-HT 3 receptors are important for the serotonergic regulation of short-term synaptic plasticity at parallel fiber-Purkinje cell synapses during the early postnatal sensitive period and regulate the maturation state of these synapses (Oostland et al, 2011).…”

“…5-HT 3 receptors are important for the serotonergic regulation of short-term synaptic plasticity at parallel fiber-Purkinje cell synapses during the early postnatal sensitive period and regulate the maturation state of these synapses (Oostland et al, 2011). They further regulate the time course of early postnatal morphological maturation of Purkinje cells as indicated by higher dendritic length and complexity in 5-HT 3 receptor knock-out mice and in vitro after treatment with a 5-HT 3 receptor antagonist (Oostland et al, 2013). 5-HT 3 receptor knock-out animals further show delayed climbing-fiber elimination (Oostland et al, 2013).…”

“…They further regulate the time course of early postnatal morphological maturation of Purkinje cells as indicated by higher dendritic length and complexity in 5-HT 3 receptor knock-out mice and in vitro after treatment with a 5-HT 3 receptor antagonist (Oostland et al, 2013). 5-HT 3 receptor knock-out animals further show delayed climbing-fiber elimination (Oostland et al, 2013). However, morphology and physiology of Purkinje cells in 5-HT 3 receptor knock-out mice appears normal in adult mice, thus indicating a narrow postnatal time window of serotonergic, 5-HT 3 receptor-mediated regulation of cerebellar maturation and connectivity (Oostland et al, 2013).…”

“…5-HT 3 receptor knock-out animals further show delayed climbing-fiber elimination (Oostland et al, 2013). However, morphology and physiology of Purkinje cells in 5-HT 3 receptor knock-out mice appears normal in adult mice, thus indicating a narrow postnatal time window of serotonergic, 5-HT 3 receptor-mediated regulation of cerebellar maturation and connectivity (Oostland et al, 2013). Further research might explore a function of 5-HT 3 receptors in the development of early life motor coordination and learning.…”

Maturation, Refinement, and Serotonergic Modulation of Cerebellar Cortical Circuits in Normal Development and in Murine Models of Autism

“…Interestingly, the time window of 5-HT 3 receptor expression corresponds to the period during which PC dendrites develop [140]. The involvement of 5-HT 3 receptors in controlling the morphological maturation of PCs has been clearly demonstrated by Oostland et al [139] in slices of 5-HT 3A R knockout mice at P9 and in organotypic slice cultures treated at P8 with a 5-HT 3 R antagonist. In both models, PCs show a higher dendritic length and complexity with respect to the control condition.…”