A working model for hydrocephalus-induced alterations in NKCC1 cotransporter expression in CP: Ion transport across basolateral and apical surfaces is driven by transmembrane ion gradients [74, 83]. Normally the net transport of Na, K, Cl, and HCO3 from choroid cell into CSF is integral to CSF production [5, 7]. However, we postulate that when CSF formation is inhibited by various neurohumoral agents there is stimulated (+) inward NaK2Cl flux from CSF into the cell; this would increase cytoplasmic Na and Cl concentration  thus creating a less favorable ion gradient for basolateral uptake of Na and Cl from plasma. Consequently, there is inhibited (-) basolateral ion uptake, and sequentially, reduced apical extrusion of Na into CSF . Net effect = decreased CSF formation. Consistent with this idea are observations of enhanced expression of CP NKCCl in congenital hydrocephalus  and AD (Fig. 4), both of which are generally associated with lower rates of CSF formation. Agents in Table 3 (e.g., Ang II) simultaneously stimulate the inward and outward arms of NKCC1, but the former three times the latter, resulting in net inward flux of ions [discussed in ref. 93]. The model thus vectorially emphasizes the inward arm of the NKCC1 (large arrowheads) as the one primarily stimulated by agents that suppress CSF formation. We hypothesize that in hydrocephalus, with increased intracranial pressure and/or ventriculomegaly, there is an associated attenuation of fluid output by CP.