A major function of the cerebellum is motor coordination and maintenance of balance. Dysfunction of the cerebellum, either as a consequence of a hereditary disorder or acquired deficiency, results in uncoordinated movement (ataxia). There is presently no cure for any of the hereditary ataxias, and there are few effective therapeutic options for ataxia in general. However, during the last two decades serotonergic agonists have been shown to be therapeutically effective in reducing the symptoms of a wide variety of cerebellar ataxias. The mechanism of action of serotonergic drugs is not understood. Given the therapeutic utility of serotonin it is important to delineate its mechanism of action in the cerebellum as a first step towards improving its therapeutic use in ataxia. The goal of this proposal is to delineate the effects of serotonergic drugs on cerebellar Purkinje cells. In particular, we will test the hypothesis that serotonin regulates the trafficking of AMPA/Kainate receptors in these neurons.
A major function of the cerebellum is motor coordination and maintenance of balance. Dysfunction of the cerebellum, either as a consequence of a hereditary disorder or acquired deficiency, results in uncoordinated movement (ataxia). There is presently no cure for any of the hereditary ataxias, and there are few effective therapeutic options for ataxia in general. However, during the last two decades serotonergic agonists have been shown to be therapeutically effective in reducing the symptoms of a wide variety of cerebellar ataxias. The mechanism of action of serotonergic drugs is not understood. Given the therapeutic utility of serotonin it is important to delineate its mechanism of action in the cerebellum as a first step towards improving its therapeutic use in ataxia. The goal of this proposal is to delineate the effects of serotonergic drugs on cerebellar Purkinje cells.
| Heck, Detlef H; De Zeeuw, Chris I; Jaeger, Dieter et al. (2013) The neuronal code(s) of the cerebellum. J Neurosci 33:17603-9 |
| Park, Sung-min; Tara, Esra; Khodakhah, Kamran (2012) Efficient generation of reciprocal signals by inhibition. J Neurophysiol 107:2453-62 |
| Medina, Javier F; Khodakhah, Kamran (2012) Neuroscience: Spikes timed through inhibition. Nature 481:446-7 |
| Fremont, Rachel; Khodakhah, Kamran (2012) Alternative approaches to modeling hereditary dystonias. Neurotherapeutics 9:315-22 |
| Dizon, Maria Johanna; Khodakhah, Kamran (2011) The role of interneurons in shaping Purkinje cell responses in the cerebellar cortex. J Neurosci 31:10463-73 |
| Calderon, D Paola; Fremont, Rachel; Kraenzlin, Franca et al. (2011) The neural substrates of rapid-onset Dystonia-Parkinsonism. Nat Neurosci 14:357-65 |
| Alviña, Karina; Khodakhah, Kamran (2010) KCa channels as therapeutic targets in episodic ataxia type-2. J Neurosci 30:7249-57 |
| Walter, Joy T; Dizon, Maria-Johanna; Khodakhah, Kamran (2009) The functional equivalence of ascending and parallel fiber inputs in cerebellar computation. J Neurosci 29:8462-73 |
