Ataxia (uncoordinated movement) is a debilitating disorder that interferes patients' ability to perform activities of daily living. Ataxia is caused by dysfunction of the cerebellum, a brain area involved in motor coordination and maintenance of balance. There are few therapies available for treatment of ataxia, and the ones used, such as serotoninergic agents, have limited efficacy often only in a subset of patients. Thus, there is a real need for new and improved therapeutic approaches for the management and treatment of ataxia. A major cause of cerebellar dysfunction is abnormal Purkinje cell activity. Purkinje cells, the sole output of the cerebellar cortex, are intrinsically active cells that integrate synaptic input from over 150,000 parallel fiber synapses and one climbing fiber. Serotonin (5-HT) has excitatory, inhibitory, or biphasic effects on firing rate of Purkinje cells. Similarly, serotonin depresses and potentiates parallel fiber-Purkinje cell synaptic transmission, and affects the climbing fiber-Purkinje cell synaptic transmission. The mechanisms by which serotonin causes these opposing effects are not understood. Nevertheless, because serotoninergic drugs are promising for the treatment of ataxia, it is important to delineate the mechanism by which they modulate cerebellar function. Serotoninergic drugs that have been most efficacious in lessening motor dysfunction were chosen to target the 5-HT1A receptor. However, these drugs can also activate 5-HT7 receptors. In the cerebellar cortex, 5-HT1A and 5-HT7 receptors are localized only to Purkinje cells and parallel fibers. Because 5-HT1A and 5-HT7 receptors typically have opposing effects on firing and synaptic transmission, it is plausible that the limited efficacy of serotoninergic drugs used to treat ataxia is due to activation of multiple receptors that elicit opposing effects on cerebellar function. Thus, in order to improve the therapeutics for ataxia, it is important to delineate how serotonin alters cerebellar function. The goal of this proposal is to elucidate how selective activation of 5-HT1A and 5-HT7 receptors alters Purkinje cell intrinsic firing and excitatory synaptic transmission onto Purkinje cells. To do so, this proposal uses electrophysiology to record from Purkinje cells in acutely prepared cerebellar slices.
Aim 1 elucidates how selective 5-HT1A and 5-HT7 receptor activation affects Purkinje cell intrinsic firing. In addition, we will examine the therapeutic efficacy of selective serotonergic agonists that alter Purkinje cell activity in a mouse model of spinocerebellar ataxia type 3.
Aim 2 delineates the effect of selective 5-HT1A and 5-HT7 receptor activation on parallel fiber and climbing fiber synaptic transmission, the pre- or post-synaptic components of any potential modulation, and long-term plasticity. Successful completion of this proposal will reveal the actions of clinically-relevant serotoninergic receptors and shed light on the regulatory role of the potent neuromodulator serotonin in the cerebellum. Furthermore, as we gain a better understanding of cerebellar function in different types of ataxia, and how serotonin modulates the cerebellar cortex, future studies will be better poised to design rational therapies to treat ataxia.
Dysfunction of the cerebellum, a brain region involved in motor coordination and maintenance of balance, leads to ataxia (uncoordinated movement), for which there are currently no effective treatments. However, serotoninergic drugs have had modest efficacy. With an eye towards improving their utility in ataxia, this project will delineate the consequence of activation of serotoninergic pathways on cerebellar function.
