Our research is focused on biophysical properties of the brain extracellular space and on glia, a key player likely to regulate the extracellular transport and distribution of ions, signaling molecules, and therapeutic agents.
Brain cells are surrounded by the extracellular space (ECS) comprised of narrow interconnected channels. The ECS accommodates diffusion of ions and signaling molecules, and it is an exclusive route for the interstitial transport of polymer-based drug carriers, therapeutic proteins, and virus-enclosed genes. We know that these processes are primarily mediated by diffusion but we lack the knowledge on which biophysical parameters of the ECS determine where and how fast these substances diffuse. One hypothesis is that the ECS contains dead-space microdomains (DSM) that can significantly slow down the diffusion process (Figure 1). This hypothesis challenges the commonly held views that the ECS is homogeneous, passive and uninteresting, explains why the transport of molecules in the ECS is so slow, and identifies a new role of glia.
The ECS is filled with an ionic solution along with macromolecules of the extracellularmatrix, negatively-charged proteoglycans and glycoproteins. It is plausible that there is a charge-based interaction between matrix and diffusing charged molecules. Indeed, we recently found that the diffusion of divalent cation calcium is slowed down due to the interaction with chondroitin sulfate proteoglycan (Figure 2). This finding is ofphysiological importance given the fundamental role of calcium and chondroitin sulfate proteoglycans in cell migration, axonal sprouting, and regeneration.
The main experimental tools used in the laboratory are optical imaging, ion-selective microelectrodes, and electrophysiology. These are complemented by Monte Carlo simulations of the diffusion process (Figure 3).
SELECTED RECENT PUBLICATIONS
1. Xiao, F., Nicholson, C., and Hrabetova, S. Diffusion of flexible random-coil polymers measured in anisotropic brainextracellular space by integrative optical imaging. Submitted.
2. Hrabetova, S. and Nicholson, C. (2007). Biophysical properties of brain extracellular space explored with ion-selective microelectrodes, integrative optical imaging and related techniques. In: Electrochemical Methods for Neuroscience, edited by Michael AC and Borland LM. Boca Raton: CRC Press, Taylor Francis Group, pp: 167-204.
3. Hrabetova, S. (2005). Extracellular diffusion is fast and isotropic in the stratum radiatum of hippocampal CA1 region in rat brain slices. Hippocampus 15: 441-450.
4. Thorne, R.G., Hrabetova, S., and Nicholson, C. (2005). Diffusion measurements for drug design. Nature Materials 4: 713.
5. Hrabe, J., Hrabetova, S., and Segeth, K. (2004). A model of effective diffusion and tortuosity in the extracellular space of the brain. Biophysical Journal 87: 1606-1617.
6. Hrabetova, S., and Nicholson, C. (2004). Contribution of dead-space microdomains to tortuosity of brain extracellular space. Neurochemistry International 45: 467-477.
7. Hrabetova, S., Hrabe, J., and Nicholson, C. (2003). Dead-space microdomains hinder extracellular diffusion in rat neocortex during ischemia. Journal of Neuroscience 23: 8351-8359.
8. Kume-Kick, J., Mazel, T., Vorisek, I., Hrabetova, S., Tao, L., and Nicholson, C. (2002). Independence of extracellular tortuosity and volume fraction during osmotic challenge in rat neocortex. Journal of Physiology 542: 515-527.
9. Hrabetova, S., Chen, K.C., Masri, D., and Nicholson, C. (2002). Water compartmentalization and spread of ischemic injury in thick-slice ischemia model. Journal of Cerebral Blood Flow and Metabolism 22: 80-88.
10. Hrabetova, S. and Nicholson, C. (2000). Dextran decreases extracellular tortuosity in a thick-slice ischemia model. Journal of Cerebral Blood Flow and Metabolism 20: 1306-1310.
List of Publications (Pub Med)