Browsing by Subject "Purkinje Cells"
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Item Modulating Calcium Signaling Pathways in Cerebellar Purkinje Cells Alleviates Spinocerebellar Ataxia 2(2012-07-16) Kasumu, Adebimpe Wakila; Bezprozvanny, IlyaSpinocerebellar ataxia 2 (SCA2) is a neurodegenerative disorder characterized by progressive ataxia. SCA2 results from the polyglutamine expansion in the cytosolic protein ataxin-2 (Atx2). Cerebellar Purkinje cells (PC) are primarily affected in SCA2, but the cause of PC dysfunction, PC death and motor incoordination in SCA2 is poorly understood. It has been reported that mutant, but not wild type Atx2, specifically binds to the inositol 1,4,5-trisphosphate receptor (InsP3R) and increases its sensitivity to activation by IP3. Thus, this toxic gain-of-function of Atx2 results in supranormal calcium (Ca2+) release from the PC endoplasmic reticulum and may play a key role in the development of SCA2 pathology. The primary focus of this dissertation will be to further elucidate the underlying mechanism of SCA2 pathogenesis, identify therapeutic targets and develop a potential treatment of SCA2. The first part of this dissertation will test the hypothesis that suppressing InsP3R-mediated Ca2+ signaling alleviates age-dependent dysfunction, and degeneration of PCs in SCA2 mice. The second part of this dissertation will focus on testing the efficacy of novel compounds that modulate calcium-activated potassium (SK) channels in the symptomatic treatment of SCA2. I conclude from this work that supranormal InsP3--Ca2+ signaling plays an important role in SCA2 pathogenesis. Partial inhibition of InsP3-mediated Ca2+ signaling or regularizing PC firing with SK channel modulators could provide therapeutic benefit for the patients afflicted with SCA2 and possibly other SCAs.Item The Role of Kv3.3 Voltage-Gated Potassium Channel Expression in Cerebellar Purkinje Cells in Motor Coordination(2009-01-14) Hurlock, Edward Clifton, IV; Joho, RolfI examined the role of the Kv3.3 voltage-gated potassium channel (Kv) subunit encoded by the Kcnc3 gene in cerebellar Purkinje cells in determining the properties of complex spikes and in motor coordination. Kv3 channels (Kv3.1-Kv3.4) enable high-frequency firing by activating and deactivating rapidly during and after action potentials, respectively. Kv3.3 subunits are expressed in distinct neuronal cell-types in regions throughout the CNS including the cerebellum, an area important for motor control. Kcnc3-null mice exhibit a reduced frequency and broadening of spikes in Purkinje cells as well as ataxia, as in spinocerebellar ataxia type 13 (SCA13) patients who carry mutations in KCNC3. In contrast to Purkinje cells, in other neuronal cell types Kv3.3 is co-expressed with considerable levels of other Kv3 subunits that potentially complement the loss of Kv3.3, suggesting that Purkinje cellular Kv3.3 function may be important for motor coordination. I restored expression of the Kv3.3b splice variant specifically in Purkinje cells by crossing transgenic mice that express Kv3.3b under the control of the tetracycline transactivator with a line expressing the latter exclusively in Purkinje cells on a Kcnc3-null background. Whole-cell recordings in slices at the resting potential of complex spikes in Purkinje neurons revealed weakened bursts but lengthened simple spike pauses thereafter in Kcnc3-null mice. Restoration of Kv3.3 completely rescued all spike parameters and sufficed to rescue motor coordination measured by counting slips traversing a 1-cm beam and recording lateral deviation of gait on a force plate actometer. The Kcnc3-null mice heterozygous for Kcnc1 were partially rescued. Gait analysis indicated the ataxia arises from hypermetria not gait ataxia. When Kcnc1 alleles are additionally ablated gait ataxia appears. Spikes in large, glutamatergic deep cerebellar nuclear (DCN) neurons, which express all four Kv3 units, broaden concurrently, but remain largely normal in Kcnc3-null mice, suggesting functional redundancy here could underlie severe ataxia in Kcnc1/Kcnc3 double-null mutants. Therefore, Kv3.3 function in Purkinje neurons is sufficient to account for the hypermetric Kcnc3-null phenotype and impaired complex spiking represents a potential underlying mechanism in addition to broadened, decelerated simple spiking. The behavioral rescue, fast spiking in DCN neurons and normal gait require Kcnc1.