FIGURE 11.

VLDs and ECS in the brain. Based on experimental and theoretical studies of brain slice ECS, Chen and Nicholson (2000) postulate that shrinkage creates ECS “lakes.” They tested ECS/cytoplasm ratios of 0.13, 0.16, 0.18, and 0.22; the geometry they used is as shown along the top panel. Shrinkage is seen as causing cells to mutually pull away from each other. Although surface area is tacitly depicted as regulated (it rises and falls with swelling and shrinking, respectively), this is deemed not relevant to changing ECS tortuosity. However, what if, 1), cell-cell contacts are mostly maintained, and 2), surface area regulation generates dilated invaginations akin to VLDs? Then it would seem appropriate to recast Chen and Nicholson along the lines suggested at bottom. We labeled the ECS/cytoplasm = 0.16 situation as “normal” simply for convenience, since we can then use the 0.13 situation as “swollen.” A “shrink” (using artistic license to add VLDs) brings this same 0.16 diagram to an ∼0.22 situation. New ECS diffusion traps (in the guise of VLDs) still appear during swell/shrink perturbations, but surface area regulation is explicit and cell-cell contacts are not ruptured as cells shrink. “Normal” (ECS/cytoplasm = 0.16) is provided at bottom, with nascent surface invaginations which allow for reversible swell/shrink perturbations. Alternatively, we could have tacitly assumed mechanically-accessible endomembrane stores to allow for swelling (see Morris and Homann, 2001). Such stores are implicit in the Chen and Nicholson model, but they (implicitly) respond instantly and perfectly to swell/shrink perturbations and so are ignored with regards to tortuosity. Cell-cell adhesions are also implicit in Chen and Nicholson, but are depicted as being extremely (perhaps abnormally?) extensible. Putting surface area adjustment along the lines shown here into the Chen and Nicholson model should, we suspect, strengthen its central message—namely, that shrinkage causes increased ECS tortuosity. For intact tissues, however, it remains to be demonstrated if either scenario pertains. If they do, then regions where hyperactive neurons and glia are deploying volume regulatory machinery should transiently exhibit both small VLDs and localized tortuosity increases.