The choroid plexus epithelial cells and the arachnoid membrane form the blood—cerebrospinal fluid barrier

The choroid plexus is a vascular tissue found in all cerebral ventricles (Fig. 32-5). The functional unit of the choroid plexus, composed of a capillary enveloped by a layer of differentiated ependymal epithelium, is shown in Figure 32-6. Unlike the capillaries that form the blood—brain barrier, choroid plexus capillaries are fenestrated and have no tight junctions. The endothelium, therefore, does not form a barrier to the movement of small molecules. Instead, the blood—CSF barrier at the choroid plexus is formed by the epithelial cells and the tight junctions that link them. The other part of the blood—CSF barrier is the arachnoid membrane, which envelops the brain. The cells of this membrane also are linked by tight junctions.

Figure 32-5

Blood—CSF barrier. The capillaries in the choroid plexus differ from those of the brain in that there is free movement of molecules across the endothelial cell through fenestrations and intercellular gaps. The blood—CSF barrier is at the (more...)

Figure 32-6

Circulation of CSF. CSF (gray) is secreted by the choroid plexus present in the cerebral ventricles and by extrachoroidal sources. It subsequently circulates through the ventricular cavities and into the subarachnoid space. Absorption into the venous (more...)

Cerebrospinal fluid is secreted primarily by the choroid plexus

The major site of CSF formation is the choroid plexus, and from a morphological viewpoint, the epithelial cells of this tissue are similar to other secretory cells. There is also some extrachoroidal secretion, which may result from ion transport by brain capillaries, as discussed above. In humans, the rate of CSF secretion is 0.3 to 0.4 ml/min, about one-third the rate at which urine is formed. The total volume of CSF is estimated to be 100 to 150 ml in normal adults, such that CSF is replaced totally three or four times each day. Several constituents are maintained at concentrations different in CSF from those in plasma (Table 32-1), indicating that CSF is not simply a protein-free ultrafiltrate of plasma. Instead, CSF production by the choroid plexus is driven by active ion transport that results in a net secretion of Na⁺ and Cl⁻, the main ionic constituents of CSF. The exact mechanisms involved have yet to be determined fully, but Figure 32-7 represents one model.

Figure 32-7

Model of ion transport at the choroid plexus epithelium. Net transport of Na⁺ and Cl⁻ across the epithelium results in the secretion of CSF. Cl⁻ efflux from the epithelium to CSF is mediated by a cotransporter. It is uncertain whether (more...)

In contrast to most epithelia, Na,K-ATPase is found on the apical, or CSF-facing, microvilli of the choroid plexus [23]. Ouabain, an inhibitor of Na,K-ATPase, reduces CSF secretion. Na,K-ATPase is probably the main transporter of Na⁺ from the epithelium to the CSF. It also provides the electrochemical gradient for basolateral, or blood-facing, Na⁺ entry into the epithelium, which probably occurs via a Na⁺/H⁺ antiport system (see Chap. 5).

Cl⁻ influx into the epithelium is via a Cl⁻/HCO⁻₃ exchanger on the basolateral membrane [24]. This exchanger can be inhibited directly with stilbenes or indirectly using acetazolamide, an inhibitor of carbonic anhydrase which reduces the intracellular production of HCO⁻₃. Cl⁻ efflux from the epithelium to the CSF is primarily via a cotransporter, which is either of the K⁺/Cl⁻ or Na⁺/K⁺/Cl⁻ type [25]. This cotransporter can be inhibited by furosemide and bumetanide. Therapeutically, acetazolamide and furosemide are used to decrease the rate of CSF formation in hydrocephalus. Acetazolamide is generally a more effective agent at decreasing CSF production. This may reflect the involvement of a cotransporter in moving ions from CSF to the epithelium (Fig. 32-7).

The choroid plexus receives a number of different forms of innervation, most notably a sympathetic input from the superior cervical ganglia. It also has many hormone receptors [26]. For example, the choroid plexus epithelium has a tenfold greater density of 5-hydroxytryptamine (5-HT)_2C receptors than any other brain tissue, although it does not appear to receive direct serotonergic innervation. A number of these neuroendocrine mechanisms modify choroid plexus blood flow or solute transport by the epithelium, indicating their potential role in controlling CSF secretion rate or composition.

Cerebrospinal fluid circulates through the ventricles, over the surface of the brain, and is absorbed at the arachnoid villi and at the cranial and spinal nerve root sheaths

The CSF circulation is from the lateral ventricles through the foramina of Monro into the third ventricle, the aqueduct of Sylvius, and then into the fourth ventricle. The fluid passes from the fourth ventricle through the foramina of Luschka and Magendie to the cisterna magna and then circulates into the cerebral and spinal subarachnoid spaces (Fig. 32-5).

There is evidence that absorption of CSF by the arachnoid villi occurs by a valve-like process, permitting the one-way flow of CSF from the subarachnoid spaces into the venous sinuses. CSF absorption does not occur until CSF pressure exceeds the pressure within the sinuses. Once this threshold is reached, the rate of absorption is proportional to the difference between CSF and sinus pressures. A normal human can absorb CSF at a rate up to six times the normal rate of CSF formation with only a moderate increase in intracranial pressure.

If obstructions occur at the foramina between the ventricles, the ventricle upstream from the obstruction will enlarge, producing obstructive hydrocephalus. Occasionally, disease processes affect CSF removal. For example, obliteration of the subarachnoid space by inflammation or thrombosis of the sinuses will prevent clearance of fluid. When this occurs, CSF pressure increases and hydrocephalus develops without obstruction of the ventricular foramina. This is called communicating hydrocephalus.

The choroid plexus is the major route of blood—brain barrier exchange for some compounds

The movement of substances from the blood into the CSF is, in many ways, analogous to that from the blood into the brain, with many of the same transporters present in both tissues. Quantitatively, however, there are major differences between transport by the choroid plexus and by the blood—brain barrier. Thus, in terms of O₂, CO₂, glucose and amino acid entry into the brain, the blood—brain barrier predominates. For some other compounds, however, the choroid plexus is the major site of entry. This is the case for Ca²⁺, where the CSF influx rate constant is tenfold greater than the blood—brain barrier value. This reflects the role of the choroid plexus in not only CSF but also brain Ca²⁺ homeostasis. The choroid plexus also may be involved in the transport of hormones into the CSF or may be a source of those hormones. For example, the choroid plexus may secrete insulin-like growth factor-II into the CSF; it also produces and secretes transthyretin, a carrier of thyroxine and retinol, into the CSF [26].

Other active transport systems in the choroid plexus are linked to the efflux of specific solutes [27]. For example, iodide and thiocyanate are transported from the CSF by saturable carrier mechanisms that can be competitively inhibited by perchlorate. This system must be active because transport can be carried out against unfavorable electrochemical gradients. Another important transport system removes weak organic acids from the CSF. Among the molecules cleared by this mechanism are penicillin and neurotransmitter metabolites, such as homovanillic acid and 5-hydroxyindoleacetic acid. This clearance system, which transports against an unfavorable CSF to blood gradient, is saturable and inhibited by probenecid. Clearance of organic acids by a probenecid-sensitive transport mechanism also may occur across the blood—brain barrier in brain capillaries.

The composition of the CSF when it enters the subarachnoid space may be modified by the arachnoid membrane. This tissue is part of the blood—CSF barrier and, like the choroid plexus and the cerebral capillaries, may not be a purely passive barrier but capable of actively modifying CSF composition.

Cerebrospinal fluid has a number of functions

A number of functions have been ascribed to the CSF [28]. The fluid-filled system around the brain has a buoyancy effect that may protect the brain from injury. Also, the rigidity of the skull means that increases in brain volume, such as those that occur from vasodilation or parenchymal cell swelling, could cause marked rises in intracranial pressure. The fluid in the CSF system, which can be displaced, limits such changes in pressure. Similarly, if the brain is dehydrated, the CSF acts as a source of fluid to rehydrate it.

As described above, the CSF system is the major source of entry of a number of substances into the brain. Why certain substances should enter via the blood—CSF barrier while others enter at the blood—brain barrier is uncertain. It might reflect the difference in the passive permeability of the two barriers since the tight junctions of the blood—CSF barrier are quantitatively leakier than those of the blood—brain barrier. Alternately, it may reflect the requirements of regions adjacent to the ventricular system.

The combination of bulk absorption of solute and solvent by the arachnoid villi and the selective removal of molecules by the choroid plexus means that there can be a concentration gradient for molecules reaching the interstitial fluid of the brain to diffuse into the CSF. Those molecules are then cleared by bulk flow or active transport. This function of the CSF, known as its sink action, helps to maintain the low concentration of many substances in both brain and CSF compared with plasma concentrations.

The CSF system also may play a role in signal transduction. It may provide a route for hormones to move within the brain, but it also may be a route of communication from the brain to the rest of the body. The bulk flow of CSF along the optic and olfactory nerves drains through lymphatic tissue, and antigenic material in the CSF may produce a systemic immune reaction.