The cerebellar mechanism of secretin in modulating mouse motor coordination and motor learning behaviors

• Main Authors: Zhang, Li, 張力
• Language: English
• Published: The University of Hong Kong (Pokfulam, Hong Kong) 2014
• Subjects: Motor learning; Secretin
• Online Access: http://hdl.handle.net/10722/207477

Motor coordination and motor learning processes are vital for animal survival. Both functions require the participation of cerebellar Purkinje neurons, which are the integrating center as they receive both excitatory and inhibitory inputs from various neurons and send out the sole inhibitory output of cerebellar cortex. Secretin, a classical peptide hormone, has been shown previously as a retrograde factor to up-regulate GABAergic inhibitory transmission on basket-Purkinje cell synapses in rats. In behavioral perspectives, there have been studies reporting changes of motor function, anxiety level, spatial memory and social interactions after application or deprivation of secretin. Based on current knowledge, secretin is hypothesized to modulate mouse motor coordination and motor learning behaviors through its effects on Purkinje neurons. To test this hypothesis, a Purkinje cell-specific secretin gene knockout moue model (Pur-Sct-/-) has been developed using Cre-Loxp recombination technique. Using immunohistochemical staining and in situ hybridization, secretin expression has been shown to be specifically eliminated in Purkinje neurons. Pur-Sct-/- mice had intact general motor ability and anxiety level in an open field. Neuromuscular strength of Pur-Sct-/-mice was impaired compared to wild type littermates in wire hanging test. Motor coordination ability was compromised as shown by vertical climbing and rotarod tasks. Further tests using repeated training on rotarod suggested impaired motor learning ability. All these behavioral changes have also been observed in secretin-null (Sct-/-) and secretin receptor-null (Sctr-/-) mice, suggesting that normal motor control and motor learning depend on integrity of secretin-secretin receptor axis in cerebellum. Postnatal neural developmental study revealed later occurrence of two motor reflexes –righting and negative geotaxis –in Pur-Sct-/-juveniles. Motor deficits in rotarod tasks persisted across mice aging from month 2 to month 9 while wire hanging impairments occurred early in Pur-Sct-/-. Secretin thus may also play a role in early postnatal cerebellar development and neural protection in mature cerebellum. To investigate the underlying mechanism, Purkinje neurons were voltage-clamped for current recording. Secretin potentiated both spontaneous and miniature inhibitory postsynaptic currents (sIPSC and mIPSC) in wild type Purkinje cells. InPur-Sct-/- and Sctr-/- mice, basal levels of sIPSC and mIPSC were significantly decreased, suggesting a role of endogenous secretin in maintaining cerebellar inhibitory transmission. The exogenous application of secretin restored IPSC in Pur-Sct-/- but not in Sctr-/- mice to comparable wild type levels, indicating the specific binding of Purkinje-derived secretin and secretin receptor underlyingthis inhibitory potentiation. In summary, secretin released in Purkinje neurons has significant role in maintaining normal motor coordination and motor learning functions. Secretin also participates in the facilitation of inhibitory transmission on interneuron-Purkinje synapses. This inhibitory potentiation is likely to coordinate motor behaviors, although further in vivo studies are required for substantiation. This study has demonstrated the function of secretin in modulating mouse motor coordination and motor learning behaviors, and in Purkinje neuron inhibitory transmission, suggesting its potential usage in drug development against cerebellar-related motor disorders. === published_or_final_version === Biological Sciences === Doctoral === Doctor of Philosophy