CNS regulation of cell volume
Presenter: J. Verbalis, MD (Georgetown University)
In this lecture, Dr. Verbalis aimed to explain some of the adaptive and de-adaptive mechanisms occurring in neurons during water stress. He started off with a slide showing the powerful effects of the brain’s compensatory mechanisms against changes in cell volume. Acute changes in brain cell volume leads almost universally to stupor/coma (near 100%); chronic changes in brain cell volume, when adaptive mechanisms have had time to kick in, drops the probability of stupor/coma down to 6%.
A number of adaptive mechanisms exist in neuronal cells to mitigate cell swelling in hyponatremia. These mechanisms mainly rely on the extrusion/degradation of cytosolic osmoles. In the brain, such osmoles are of 2 types: electrolytes and osmolytes. In the former, Na+, K+, and Cl– are actively pumped out of the cell. Electrolytes account for about 67% of the intraneuronal osmoles, and amongst these 3, brain chloride (Cl–) is the electrolyte that is pumped out in greatest percentage. How are these ions eliminated from the cytosol? The answer isn’t well understood, but may have something to do with intracellular Ca2+. While Na+, K+, and Cl– are actively pumped out of the cell, Ca2+ enters the cell in a manner that is proportional to the degree of cell swelling (or cell stretching). Stretch-activated channels (SAC’s) are activated in direct proportion to the degree of cell swelling, which causes an influx of Ca2+. What happens inside the cell, and how Ca2+ plays a role in eliminating intracellular Na+, K+, and Cl–, is unclear.
Osmolytes make up the remaining 33% of intracellular osmoles, and consist of creatinine, glutamine, glutamate, taurine, and inositol (to name a few). Rather than active elimination from the intracellular space, these osmolytes are degraded via mechanisms that aren’t clearly understood. Dr. Verbalis showed a series of graphs indicating the drop in concentration of each of these osmolytes as serum Na+ levels dropped (hyponatremia). These adaptive mechanisms require time (days) in order to be fully effective, but when they are completed, the patient is able to survive. However, fine neurologic testing (specifically, fine motor skills) during periods of severe hyponatremia indicates that an osmole-depleted brain is not a normal brain. Dr. Verbalis emphasizes this point a few more times — osmole-depleted brains appear to be normal, but in fact are “quasi”-normal and can be excited with the mild external stimuli (such as mild hypoglycemia, mild hypoxia).
One final mechanism that is involved in regulating brain cell volume is the extrusion of water from within the cell. The main channel in the brain is aquaporin-4 (AQP4), found both at the blood-brain and brain-CSF interfaces. AQP4 channels allow for bidirectional movement of water; once open, water moves through these channels in a manner predicted by the osmotic pressure gradient. Thus it is not exactly clear what deleterious effects these channels can have on brain cell swelling when they are not functioning correctly (that is, open channels when they should be closed).
De-adaptive measures are simply the reversal of the above-mentioned adaptive mechanisms. This mechanism requires days to occur and is primarily dependent on the regeneration of osmolytes. One question that was not answered in this lecture is why de-adaptive measures rely heavily on the regeneration of osmolytes rather than the influx of electrolytes, given that osmolytes account for only 33% of the intracellular osmoles. Are these osmolytes, collectively, contributing to the intracellular osmolarity to a greater degree than the electrolytes, despite being quantitatively lower in concentration? This would be tough given that Na+ is a powerful contributor to intraneuronal osmolarity.
Finally, Dr. Verbalis broached the topic of chronic hyponatremia (for 3 months or longer). He showed data from his lab of the effects on bone. Many forget that 33% of total body sodium is stored in bone and that osteoclasts have a sodium sensing feature, akin to calcium sensing. Mice who live with hyponatremia for months have significant bone demineralization (as shown on DEXA scanning). These osteoclasts sense a deficiency in total body sodium (for an unclear mechanism given that the initial insult in hyponatremia is excess water and not necessarily a reduction in total body sodium) and release bone-stores of sodium. The kidney, however, detects the increase in total body sodium and affects a natriuresis. As a result, a vicious cycle begins with an increasing amount of bone sodium released from the bone. According to Dr. Verbalis, the chronic hyponatremic mouse is the most striking animal model for osteoporosis known thus far.