SYNAPTIC ORIGINS OF CEREBELLAR DISEASE

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DESCRIPTION (provided by applicant): The cerebellum is essential for motor behavior. Motor behavior is severely disrupted in ataxia, dystonia, and tremor. These diseases are defined by very distinct motor impairments, which raises an intriguing problem because the cerebellar circuitry that's affected is the same in each case. For instance, all Purkinje cells receive the same inputs, yet their outputs instigate all three diseases. The main focus of this research is to understanding how the same circuitry is capable of causing several different diseases. To address this problem we postulated that in each disease circuit behavior might be determined by how neuronal communication is altered. To test this we devised an experimental model that enables us to systematically block chemical communication in the main cerebellar synapses. Our model utilizes the Cre/loxP genetic approach to conditionally block the expression of the vesicular GABA transporter VGAT or the vesicular glutamate transporter VGLUT2 at every major synapse in the mouse cerebellum. We have generated compelling preliminary data showing that the inception of cerebellar disease may depend on damaged synapses rather than circuits. Now we would like to expand on this work by testing the hypothesis that loss of signaling at different cerebellar synapses will result in phenotypes that resemble a range of cerebellar diseases. In our first aim we will trace the path of a typical signal through the cerebellum and systematically silence each type of synapse starting from the sensory input stage through to the motor output. We will delineate how loss of synapse communication leads to motor disease by determining how each connection influences circuit morphogenesis and neuronal function, and how each one impacts motor behavior. In our second aim we will test whether obstructing synapse function during cerebellar development has a different pathogenic outcome to blocking the same synapse in the adult cerebellum. For this question we will manipulate synapses with spatial and temporal precision and then analyze circuit connectivity and neuronal function in behaving mice. This information has important consequences for therapy because different cerebellar synapses could be targeted to rescue movement in different diseases.