Expression and function of K_ir7.1 in the Murine Central nervous system

Abstract

Glia express a variety of ion channels, but the precise subtypes expressed by astrocytes and oligodendrocytes has not been fully elucidated. The Kir7.1 subtype of inwardly rectifying potassium channels (K_ir) is highly expressed in retinal pigment epithelium and has been demonstrated in Purkinje neurons of the adult rat cerebellum and pyramidal neurons of the hippocampus, but it has not previously been identified in glia. Using quantitative real time PCR, an ion channel profile for the developing mouse optic nerve was constructed and K_ir7.1 was identified as one of the major ion channels present. Immunostaining revealed widespread expression of K_ir7.1 in glia and neurons in the mouse brain with the highest expression found in optic nerve oligodendrocytes. A major function of K_ir is to maintain the membrane potential of glia in the face of large ionic shifts associated with normal neuronal function and pathology. Oligodendrocytes are particularly susceptible to ischemia so the role of Kir7.1 in maintaining oligodendrocyte integrity during oxygen and glucose deprivation (ODG) in the isolated intact mouse optic nerve was examined, using the K_ir7.1 channel blocker VU590. Blockade of K_ir7.1 resulted in increased cell death of optic nerve oligodendrocytes in normoxic conditions by activating caspase -dependent apoptotic pathways and significantly augmented cell death induced by OGD. Moreover, intracellular calcium fluctuations dependent on store operated calcium entry in optic nerve glia were identified as a potential mechanism for the cellular stress induced by K_ir7.1 inhibition. The results presented within this thesis demonstrate functional expression of K_ir7.1 in glial cells, and indicate they are important in maintaining oligodendrocytic integrity in both physiological and pathological conditions.

Date of Award	Aug 2014
Original language	English
Awarding Institution	University of Portsmouth
Supervisor	Anthony Lewis (Supervisor) & Arthur Butt (Supervisor)