COM4S_M.TTF

Glial Biology Research

The research interests in this area center on the classification and function of two populations of star-shaped glial cells, astrocytes and NG2 glia, in the mammalian central nervous system (CNS). These glial cells are as numerous as neurons and are so named because most of them have a star-shaped appearance under the microscope (fig 1). Astrocytes are coupled amongst themselves through gap junction channels (fig 2) with their endfeed ensheathing neuronal synapses and surrounding blood vessels. In contrast to the better studied neurons in the CNS, the precise role of astrocytes and NG2 glia in the CNS is still largely unclear.

One focus has been on the functions of the mature form of astrocytes in the hippocampus. This cell is characterized by the expression of a large leak type potassium channel conductance. Specifically, studies are carried out to understand the molecular identities and function of potassium channels underlying this characteristic nature astrocyte electrophysiology (fig2).

We are currently asking the question whether astrocytes are heterogeneous in terms of their functional properties and gene expression in different brain regions in the developing and mature brain. Accumulation of basic information from these glial cells in vivo should shed light on what these glial cells do in the normal and pathological brain.

The techniques used in these studies include in situ patch clamp electrophysiology to study astrocyte and NG2 glia ion channels and receptors and transporters; immunocytochemical confocal microscopy for glial specific marker and protein expression identification (fig 1); and single cell RT-PCR, and microarray for identifying genes encoding the functional proteins.

Stroke Research

Stroke, resulting from the occlusion of brain arteries, is the third leading cause of death in developed countries. However, only one therapeutic strategy is currently approved. One important aspect of the research in this group is to understand whether malfunctions of astrocytes contribute to the early damage in stroke and thus are potential targets for therapy.

Astrocytic swelling is an early event in cerebral ischemia, and this leads to the activation of volume regulated anion channels (VRACs) as a pathological pathway in release glutamate (fig 3). Though glutamate is normally released as a chemical message for information processing between neurons, excessive accumulation of glutamate in the extracellular space is toxic and can cause neuronal death. Though VRACs activity can be readily recognized by electrophysiological recording, the molecular identity of this ion channel is completely unknown. Therefore, looking for VRACs channel identity and exploring effective VRACs inhibitors has been one of the research areas of our group.

The recent discovery that most of the water channels or aquaporins in the brain are to be found in astrocytes adds further interest to studying astrocytic swelling. This swelling is the main underlying condition of cytotoxic or cellular edema. An ongoing project is to understanding whether a water channel isoform, termed aquaporin 9, increases in expression in response to ischemia and is neuroprotective in stroke.

Recently, the research from this group has led to identification of tamoxifen as a very effective neuroprotectant in rat ischemic models (fig 4) as well as in an acute brain slice ischemic model. We seek to study the mechanisms of its neuroprotection in more detail in animal models and then set up a clinical trial to test its use as a neuroprotectant in stroke, as there are presently no neuroprotectants approved for such use.

The techniques applied to stroke research include in vivo rat focal ischemia model, in situ oxygen-glucose deprivation in brain slices as an in vitro ischemia model, western blotting, RT-PCR, confocal microscopy, patch clamp.

Figure 1	Figure 2
Figure 3	Figure 4