Manipulation of neuronal ion channels
The present invention provides compositions and methods for the manipulation of ion channels. For example, the present invention relates to Parkinson's and other neurological diseases and conditions, and treatments thereof. In particular, the present invention provides methods of decreasing pathophysiological high frequency neuronal bursts of Parkinson's and other neurological diseases and conditions. Methods of the present invention comprise decreasing Kv3 ion channel activity in fast-spiking neurons, including by decreasing activity of a Kv3.4 protein and by specifically targeting a Kv3.4 protein with an inhibitor.
1. A method of manipulating neuronal ion channels, comprising: transfecting a fast-spiking neuronal cell, wherein said fast spiking neuronal cell is capable of sustained high frequency discharge without significant accommodation, and wherein said cell comprises a co-assembled complex of mammalian Kv3.1, Kv3.2, Kv3.3 and Kv3.4, with a vector encoding an siRNA directed against an mRNA encoding a mammalian Kv3.4 protein wherein said siRNA is capable of inhibiting Kv3.4 expression in said cell, and wherein said inhibition of Kv3.4 expression results in a decrease in said sustained high frequency discharge in said cell but not in cells lacking said co-assembled complex.
2. The method of claim 1 , further comprising the step of transplanting said cell into a subject.
3. The method of claim 1 , wherein said frequency is greater than 100 Hz.
4. The method of claim 1 , wherein said frequency is greater than 150 Hz.
5. The method of claim 1 , wherein said mammalian Kv3.4 is rat.
6. The method of claim 1 , wherein said mammalian Kv3.4 is human.
7. A method of manipulating neuronal ion channels, comprising: transfecting a fast-spiking neuronal cell, wherein said fast spiking neuronal cell is capable of sustained high frequency discharge without significant accommodation, and wherein said cell comprises a co-assembled complex of mammalian Kv3.1, Kv3.2, Kv3.3 and Kv3.4, with a vector encoding an siRNA having a nucleic acid selected from the group consisting of SEQ ID NOs: 3 and 4, wherein said siRNA is capable of inhibiting Kv3.4 expression in said cell, and wherein said inhibition of Kv3.4 expression results in a decrease in said sustained high frequency discharge in said cell but not in cells lacking said co-assembled complex.
8. A method of treating Parkinson's disease in a subject, comprising transfecting a fast-spiking neuronal cell, wherein said fast spiking neuronal cell is capable of sustained high frequency discharge without significant accommodation, and wherein said cell comprises a co-assembled complex of mammalian Kv3.1, Kv3.2, Kv3.3 and Kv3.4, and wherein said cell is in a subject diagnosed with Parkinson's disease, with a vector encoding an siRNA directed against an mRNA encoding a mammalian Kv3.4 protein wherein said siRNA is capable of inhibiting Kv3.4 expression in said cell, and wherein said inhibition of Kv3.4 expression results in a decrease in said sustained high frequency discharge in said cell but not in cells lacking said co-assembled complex.