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.
| Thompson, Emily G; Sontheimer, Harald (2016) A role for ion channels in perivascular glioma invasion. Eur Biophys J 45:635-648 |
| Kimbrough, Ian F; Robel, Stefanie; Roberson, Erik D et al. (2015) Vascular amyloidosis impairs the gliovascular unit in a mouse model of Alzheimer's disease. Brain 138:3716-33 |
| Robert, Stephanie M; Buckingham, Susan C; Campbell, Susan L et al. (2015) SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma. Sci Transl Med 7:289ra86 |
| Robel, Stefanie; Buckingham, Susan C; Boni, Jessica L et al. (2015) Reactive astrogliosis causes the development of spontaneous seizures. J Neurosci 35:3330-45 |
| Cuddapah, Vishnu Anand; Robel, Stefanie; Watkins, Stacey et al. (2014) A neurocentric perspective on glioma invasion. Nat Rev Neurosci 15:455-65 |
| Turner, Kathryn L; Honasoge, Avinash; Robert, Stephanie M et al. (2014) A proinvasive role for the Ca(2+) -activated K(+) channel KCa3.1 in malignant glioma. Glia 62:971-81 |
| Turner, Kathryn L; Sontheimer, Harald (2014) Cl- and K+ channels and their role in primary brain tumour biology. Philos Trans R Soc Lond B Biol Sci 369:20130095 |
| Robert, Stephanie M; Ogunrinu-Babarinde, Toyin; Holt, Kenneth T et al. (2014) Role of glutamate transporters in redox homeostasis of the brain. Neurochem Int 73:181-91 |
| Turner, Kathryn L; Sontheimer, Harald (2014) KCa3.1 modulates neuroblast migration along the rostral migratory stream (RMS) in vivo. Cereb Cortex 24:2388-400 |
| Watkins, Stacey; Robel, Stefanie; Kimbrough, Ian F et al. (2014) Disruption of astrocyte-vascular coupling and the blood-brain barrier by invading glioma cells. Nat Commun 5:4196 |
Showing the most recent 10 out of 77 publications
