NSC 18319 No.

of Pages 1
3 March 2018

NEUROSCIENCE
1
LETTER TO THE EDITOR
R. F. Keep et al. / Neuroscience xxx (2018) xxx–xxx

3
2 Comment on ‘‘Role of Choroid Plexus in Cerebrospinal
4 Fluid Hydrodynamics”
5 Richard F. Keep, a Margery A. Barrand b and Stephen B. Hladky b*
a
6 Department of Neurosurgery, University of Michigan, R5018 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA
b
7 Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK
8
9

10 In their article in Neuroscience (Oreskovic et al., 2017), plexus surface area measurements of Voetmann (1949). 49
11 Oreskovic et al. downplay the role of the choroid plexus However, that study did not take into account the well- 50
12 in cerebrospinal fluid (CSF) secretion and suggest instead defined apical brush border of the choroidal epithelial cell. 51
13 that interstitial fluid (ISF) and CSF are generated by water It has been estimated based on electron microscopy tak- 52
14 filtration across the arterial capillaries in the brain par- ing the brush border into account that the choroid plexus 53
15 enchyma. They appear to dismiss both the evidence apical (CSF-facing) surface area is about half that of the 54
16 (see e.g., (Damkier et al., 2013; Spector et al., 2015)) that brain capillary network (Keep and Jones, 1990). Cell 55
17 the choroid plexuses secrete fluid and the assessment of capacitance measurements (Speake and Brown, 2004) 56
18 CSF secretion rate using techniques involving imperme- also reveal a much greater surface area than expected 57
19 ant marker substances to follow net flow of CSF out of from Voetmann’s measurements. 58
20 the ventricles (ventriculo-cisternal perfusion). Instead they Though the ion transporters and water permeability of 59
21 make the argument that since 99% of CSF volume is the blood–brain barrier could, if the transporters are 60
22 water and all other substances account for only 1%, the properly arranged, produce enough fluid to account for 61
23 choroid plexuses, if the main players in CSF secretion, CSF secretion, e.g., c. 500 ml day 1 in man, the 62
24 should also be the main sites of water entry to CSF. But available evidence does not suggest even the direction 63
25 this they argue does not square with experimental results of the net fluid movement with any certainty. On 64
26 showing water influx into CSF being controlled by AQP-4 balance, the evidence favors the view that the blood– 65
27 (which is not present in choroid plexuses but along the brain barrier secretes somewhat less fluid into the brain 66
28 vasculature) and not by AQP1 (which is present in choroid than do the choroid plexuses (Hladky and Barrand, 2016). 67
29 plexuses but not the vasculature) (Igarashi et al., 2013).
30 They feel therefore that choroid plexuses are unlikely to REFERENCES 68
31 play a major role in CSF formation. There are very large
32 unidirectional fluxes of water in and out of ISF and CSF Damkier HH, Brown PD, Praetorius J (2013) Cerebrospinal fluid 69

33 and the finding by Igarashi et al. that these depend on secretion by the choroid plexus. Physiol Rev 93:1847–1892. 70
Hladky SB, Barrand MA (2016) Fluid and ion transfer across the 71
34 the function of AQP4 is not surprising. However, it is the blood–brain and blood–cerebrospinal fluid barriers; a comparative 72
35 net flux of water across the blood–brain barrier rather than account of mechanisms and roles. Fluids Barriers CNS 13:19. 73
36 influx or efflux that must be compared with the fluid secre- Igarashi H, Tsujita M, Suzuki Y, Kwee IL, Nakada T (2013) Inhibition 74
37 tion by the choroid plexuses. The net flux across the of aquaporin-4 significantly increases regional cerebral blood flow. 75
38 blood–brain barrier is several orders of magnitude smaller NeuroReport 24:324–328. 76

39 than the unidirectional fluxes (Hladky and Barrand, 2016) Keep RF, Jones HC (1990) A morphometric study on the 77
development of the lateral ventricle choroid-plexus, choroid- 78
40 and it is not known how the net flux is affected by the func-
plexus capillaries and ventricular ependyma in the rat. Brain 79
41 tion of AQP4. Res Devel Brain Res 56:47–53. 80
42 Another argument that Oreskovic et al. use against Oreskovic D, Rados M, Klarica M (2017) Role of choroid plexus in 81
43 the idea of the choroid plexuses as a major source of cerebrospinal fluid hydrodynamics. Neuroscience 354:69–87. 82
44 CSF is their statement that ‘the contact surface between Speake T, Brown PD (2004) Ion channels in epithelial cells of the 83
45 the choroid plexus and the CSF is around 5000 times choroid plexus isolated from the lateral ventricle of rat brain. Brain 84
Res 1005:60–66. 85
46 smaller than that between the brain capillary network
Spector R, Keep RF, Snodgrass SR, Smith QR, Johanson CE (2015) 86
47 and the brain interstitium’ (Oreskovic et al., 2017). Similar A balanced view of choroid plexus structure and function: Focus 87
48 statements have in the past been based on the choroid on adult humans. Exp Neurol 267:78–86. 88
Voetmann E (1949) On the structure and surface area of the human 89
choroid plexuses. A quantitative anatomical study. Acta Anat 90
*Corresponding author.
Suppl 10:1–116. 91
E-mail address: sbh1@cam.ac.uk (S. B. Hladky).
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https://doi.org/10.1016/j.neuroscience.2018.02.029
0306-4522/Ó 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Keep RF et al. Comment on ‘‘Role of Choroid Plexus in Cerebrospinal Fluid Hydrodynamics”. Neuroscience (2018), https://doi.org/10.1016/j.neuroscience.2018.02.029