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.

Public Health Relevance

Cerebellar damage causes severe movement disorders such as ataxia, dystonia, and tremor. Patients that are affected by these disorders suffer from a range of motor disturbances that are very specific to each condition. This raises an intriguing problem because the same cerebellar circuitry is always destroyed. Our goal is to determine how damaging a common cerebellar circuit can lead to drastically different conditions. Addressing this problem is important for human health because it could lead to ways of treating multiple movement diseases by fixing a hub circuit in the motor system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS089664-01
Application #
8797650
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Riddle, Robert D
Project Start
2014-09-30
Project End
2019-06-30
Budget Start
2014-09-30
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77030
White, Joshua J; Lin, Tao; Brown, Amanda M et al. (2016) An optimized surgical approach for obtaining stable extracellular single-unit recordings from the cerebellum of head-fixed behaving mice. J Neurosci Methods 262:21-31
White, Joshua J; Arancillo, Marife; King, Annesha et al. (2016) Pathogenesis of severe ataxia and tremor without the typical signs of neurodegeneration. Neurobiol Dis 86:86-98
Sillitoe, Roy V (2016) Mossy Fibers Terminate Directly Within Purkinje Cell Zones During Mouse Development. Cerebellum 15:14-7
Leto, Ketty; Arancillo, Marife; Becker, Esther B E et al. (2016) Consensus Paper: Cerebellar Development. Cerebellum 15:789-828
Arancillo, Marife; White, Joshua J; Lin, Tao et al. (2015) In vivo analysis of Purkinje cell firing properties during postnatal mouse development. J Neurophysiol 113:578-91
Lee, Sun Kyong; Sillitoe, Roy V; Silva, Coralie et al. (2015) α-Synuclein Expression in the Mouse Cerebellum Is Restricted to VGluT1 Excitatory Terminals and Is Enriched in Unipolar Brush Cells. Cerebellum 14:516-27
Gennarino, Vincenzo A; Singh, Ravi K; White, Joshua J et al. (2015) Pumilio1 haploinsufficiency leads to SCA1-like neurodegeneration by increasing wild-type Ataxin1 levels. Cell 160:1087-98
Cerminara, Nadia L; Lang, Eric J; Sillitoe, Roy V et al. (2015) Redefining the cerebellar cortex as an assembly of non-uniform Purkinje cell microcircuits. Nat Rev Neurosci 16:79-93
Tian, Xuejun; Gala, Upasana; Zhang, Yongping et al. (2015) A voltage-gated calcium channel regulates lysosomal fusion with endosomes and autophagosomes and is required for neuronal homeostasis. PLoS Biol 13:e1002103
White, Joshua J; Arancillo, Marife; Stay, Trace L et al. (2014) Cerebellar zonal patterning relies on Purkinje cell neurotransmission. J Neurosci 34:8231-45