Medical Physiology, 3rd Edition

Brain Extracellular Space

Neurons, glia, and capillaries are packed tightly together in the CNS

The average width of the space between brain cells is ~20 nm, which is about three orders of magnitude smaller than the diameter of either a neuron or a glial cell body (Fig. 11-5). However, because the surface membranes of neurons and glial cells are highly folded (i.e., have a large surface-to-volume ratio), the BECF in toto has a sizable volume fraction, ~20%, of total brain volume. The fraction of the brain occupied by BECF varies somewhat in different areas of the CNS and increases during sleep. Moreover, because brain cells can increase volume rapidly during intense neural activity, the BECF fraction can reversibly decrease within seconds from ~20% to ~17% of brain volume.


FIGURE 11-5 Tight packing of neurons and astrocytes. This is an electron micrograph of a section of the spinal cord from an adult rat showing the intermingling and close apposition of neurons and glial cells, mainly astrocytes. Neurons and glial cells are separated by narrow clefts that are ~20 nm wide and not visible at this magnification. The BECF in this space creates a tortuous path for the extracellular diffusion of solutes. Astrocyte processes are colored. As, astrocytes; At, en passant synapses; Ax, unmyelinated axons; Ax1and Ax2, myelinated axons; Den, dendrites; f, astrocytic fibrils; nf, neurofilaments; S, synapses; SR, smooth endoplasmic reticulum. (Modified from Peters A, Palay SL, Webster H: The Fine Structure of the Nervous System. Philadelphia, WB Saunders, 1976.)

Even though the space between brain cells is extremely small, diffusion of ions and other solutes within this thin BECF space is reasonably high. However, a particle that diffuses through the BECF from one side of a neuron to the other must take a circuitous route that is described by a parameter called tortuosity. For a normal width of the cell-to-cell spacing, this tortuosity reduces the rate of diffusion by ~60% compared with movement in free solution. Decreases in cell-to-cell spacing can further slow diffusion. For example, brain cells, especially glial cells, swell under certain pathological conditions and sometimes with intense neural activity. Cell swelling is associated with a reduction in BECF because water moves from the BECF into cells. The intense cell swelling associated with acute anoxia, for example, can reduce BECF volume from ~20% to ~5% of total brain volume. By definition, this reduced extracellular volume translates to reduced cell-to-cell spacing, which further slows the extracellular movement of solutes between the blood and brain cells (Box 11-3).

Box 11-3

Cerebral Edema

Almost any type of insult to the brain causes cell swelling, which is frequently accompanied by a net accumulation of water within the brain that is referred to as cerebral edema. Cell swelling in the absence of net water accumulation in the brain does not constitute cerebral edema. For example, intense neural activity causes a rapid shift of fluid from the BECF to the intracellular space, with no net change in brain water content. In cerebral edema, the extra water comes from the blood, as shown in Figure 11-6.


FIGURE 11-6 Cerebral edema. A, In cerebral edema, the brain fluid that accumulates comes from the vascular compartment. Cell swelling due to the mere shift of fluid from the extracellular to the intracellular fluid is not cerebral edema. B, Although small increases in intracranial volume have little effect on pressure, additional increases in volume cause potentially life-threatening increases in pressure. Note that compliance (i.e., ΔVP) falls at increasing volumes.

The mechanisms by which glial cells and neurons swell are not completely understood. Neuron cell bodies and dendrites, but not axons, swell when exposed to high concentrations of the neurotransmitter glutamate. This transmitter, along with others, is released to the BECF in an uncontrolled fashion with brain injury. Activation of ionotropic glutamate receptors (see pp. 323–324) allows Na+ to enter neurons, and water and Cl follow passively. Glial cells, both astrocytes and oligodendrocytes, swell vigorously under pathological conditions. One mechanism of glial swelling is an increase in [K+]o, which is a common ionic disturbance in a variety of brain pathological processes. This elevated [K+]o causes a net uptake of K+, accompanied by the passive influx of Cl and water.

Cerebral edema can be life threatening when it is severe. The problem is a mechanical one. The skull is an inelastic container housing three relatively noncompressible substances: brain, CSF, and blood. A significant increase in the volume of CSF, blood, or brain rapidly causes increased pressure within the skull (see Fig. 11-6B). If the cerebral edema is generalized, it can be tolerated until intracerebral pressure exceeds arterial blood pressure, at which point blood flow to the brain stops, with disastrous consequences. Fortunately, sensors in the medulla detect the increased intracerebral pressure and can partially compensate by increasing arterial pressure (Cushing reflex; see p. 559). Focal cerebral edema (i.e., edema involving an isolated portion of the brain) causes problems by displacing nearby brain tissue. This abnormality may result in distortion of normal anatomical relationships, with selective pressure on critical structures such as the brainstem.

Clinical evidence of cerebral edema results directly from the increased intracranial pressure and includes headache, vomiting, altered consciousness, and focal neurological problems. Because of its long intracranial course, the sixth cranial nerve is especially vulnerable to stretching and dysfunction.

Hyperventilation is the most effective means of combating the acute increase in intracranial pressure associated with severe cerebral edema. Hyperventilation causes a prompt respiratory alkalosis (see p. 634) that is rapidly translated to an increase in the pH surrounding vascular smooth muscle, thereby triggering vasoconstriction and reduced cerebral blood flow (see p. 559). Thus, total intracranial blood content falls, with a rapid subsequent drop in intracranial pressure. Alternatively, the brain can be partially dehydrated by adding osmoles to the blood in the form of intravenously administered mannitol (see p. 131).

The BECF is the route by which important molecules such as oxygen, glucose, and amino acids reach brain cells and by which the products of metabolism, including CO2 and catabolized neurotransmitters, leave the brain. The BECF also permits molecules that are released by brain cells to diffuse to adjacent cells. Neurotransmitter molecules released at synaptic sites, for example, can spill over from the synaptic cleft and contact nearby glial cells and neurons, in addition to their target postsynaptic cell. Glial cells express neurotransmitter receptors, and neurons have extrajunctional receptors; therefore, these cells are capable of receiving “messages” sent through the BECF. Numerous trophic molecules (see p. 292) secreted by brain cells diffuse in the BECF to their targets. Intercellular communication by way of the BECF is especially well suited for the transmission of tonic signals that are ideal for longer-term modulation of the behavior of aggregates of neurons and glial cells. The chronic presence of variable amounts of neurotransmitters in the BECF supports this idea.

The CSF communicates freely with the BECF, which stabilizes the composition of the neuronal microenvironment

CSF in the ventricles and the subarachnoid space can exchange freely with BECF across two borders, the pia mater and ependymal cells. The pial-glial membrane (see Fig. 11-2, upper inset) has paracellular gaps through which substances can equilibrate between the subarachnoid space and BECF. Ependymal cells (see Fig. 11-2, lower inset) are special glial cells that line the walls of the ventricles and form the cellular boundary between the CSF and the BECF. These cells form gap junctions (see p. 45) between themselves that mediate intercellular communication, but they do not create a tight epithelium (see p. 137). Thus, macromolecules and ions can also easily pass through this cellular layer through paracellular openings (some notable exceptions to this rule are considered below) and equilibrate between the CSF in the ventricle and the BECF.

Because CSF and BECF can readily exchange with one another, it is not surprising that they have a similar chemical composition. For example, [K+] is ~3.3 mM in freshly secreted CSF and ~3 mM in both the CSF of the subarachnoid space (see Table 11-1) and BECF. The [K+] of blood is ~4.5 mM. However, because of the extent and vast complexity of the extracellular space, changes in the composition of CSF are reflected slowly in the BECF and probably incompletely.

CSF is an efficient waste-management system because of its high rate of production, its circulation over the surface of the brain, and the free exchange between CSF and BECF. Products of metabolism and other substances released by cells, perhaps for signaling purposes, can diffuse into the chemically stable CSF and ultimately be removed on a continuous basis either by bulk resorption into the venous sinuses or by active transport across the choroid plexus into the blood. For example, the choroid plexus actively absorbs the breakdown products of the neurotransmitters serotonin (i.e., 5-hydroxyindoleacetic acid) and dopamine (i.e., homovanillic acid).

The ion fluxes that accompany neural activity cause large changes in extracellular ion concentration

As discussed in Chapter 7, ionic currents through cell membranes underlie the synaptic and action potentials by which neurons communicate. These currents lead to changes in the ion concentrations of the BECF. It is estimated that even a single action potential can transiently lower [Na+]o by ~0.75 mM and increase [K+]o by a similar amount. Repetitive neuronal activity causes larger perturbations in these extracellular ion concentrations. Because ambient [K+]o is much lower than [Na+]o, activity-induced changes in [K+]o are proportionately larger and are of special interest because of the important effect that [K+]ohas on membrane potential (Vm). For example, K+ accumulation in the vicinity of active neurons depolarizes nearby glial cells. In this way, neurons signal to glial cells the pattern and extent of their activity. Even small changes in [K+]o can alter metabolism and ionic transport in glial cells and may be used for signaling. Changes in the extracellular concentrations of certain common amino acids, such as glutamate and glycine, can also affect neuronal Vm and synaptic function by acting at specific receptor sites. If the nervous system is to function reliably, its signaling elements must have a regulated environment. Glial cells and neurons both function to prevent excessive extracellular accumulation of K+ and neurotransmitters.