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

Key points center dot Serotonin 3 (5-HT3) receptors are expressed by excitatory granule cells in the cerebellum during early postnatal development. center dot Here we show a novel role for serotonin in the regulation of cerebellar postnatal development via 5-HT3 receptors. center dot Using 5-HT3A receptor knockout mice we show that 5-HT3 receptors expressed by granule cells, via the glycoprotein reelin, regulate the morphological maturation of Purkinje cells. center dot The 5-HT3A receptor knockout mice show abnormal physiological maturation of Purkinje cells and impaired short-term plasticity at the parallel fibrePurkinje cell synapse, resulting in delayed climbing fibre elimination. center dot 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 serotonin3 (5-HT3) receptors are transiently expressed by cerebellar granule cells during early postnatal development, where they modulate short-term synaptic plasticity at the parallel fibrePurkinje cell synapse. Here, we show that serotonin controls maturation of Purkinje cells in the mouse cerebellum. The 5-HT3 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-HT3A 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 fibrePurkinje cell and the climbing fibrePurkinje 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-HT3A receptor knockout mice. There was no difference between wild-type and 5-HT3A 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-HT3 receptors expressed by granule cells.