Using patch-clamp recordings of identified astrocytes in acute slices of rat hippocampus, the applicants have observed an intriguing developmental change in the relative expression of K+ channels. A switch from outwardly rectifying (Id) to inwardly rectifying K+ channels (Ir) occurs in the 2nd and 3rd postnatal week and thus closely parallels cessation of gliogenesis in hippocampus. In concert with preliminary data showing that astrocyte proliferation can be inhibited by selective pharmacological blockade or by anti-sense knockdown of Id, these findings lead us to hypothesize that differential expression of K+ channels is associated with and may be functionally linked to cell cycle progression and differentiation of astrocytes in vivo. More specifically the applicants hypothesize that: (1). The transition from dividing to non-dividing astrocyte is characterized by an obligatory change in K+ channel complement. (2). Astrocytes induced to proliferate by injury or disease transiently acquire K+ channel expression characteristic of proliferating astrocytes. (3). Changes in K+ channel expression leads to membrane depolarization and intracellular acidification, establishing a permissive ionic environment for glial proliferation. These hypotheses will be tested using a combination of patch-clamp recordings and ratiometric fluorescence imaging techniques allowing long-term measurements of changes in intracellular ion composition associated with astrocyte cell cycle progression. The applicants will investigate the role of K+ channels in spontaneous proliferation of astrocytes during gliogenesis, and in """"""""secondary"""""""" injury or disease-induced proliferation of astrocytes associated with glial scars (reactive gliosis). Collectively, the proposed studies will provide a major step towards understanding mechanisms that regulate astrocyte proliferation during normal gliogenesis and after injury and disease, and may facilitate the development of new strategies to control gliosis.
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