Vol.:(0123456789) 1 3 https://doi.org/10.1007/s00381-021-05253-1 ORIGINAL ARTICLE Cerebrospinal fluid may flow out from the brain through the frontal skull base and choroid plexus: a gold colloid and cadaverine injection study in mouse fetus Takuya Akai 1  · Toshihisa Hatta 2  · Hiromi Sakata‑Haga 2  · Seiji Yamamoto 3  · Hiroki Otani 4  · Shusuke Yamamoto 1  · Satoshi Kuroda 1 Received: 18 March 2021 / Accepted: 8 June 2021 © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021 Abstract Purpose It has been commonly accepted for a long time that the cerebrospinal fuid (CSF) drains into arachnoid granulations from the subarachnoid space to the dural venous sinus unidirectionally. However, recently, periventricular capillaries and lymphatic concepts have been introduced. The CSF moves along the perivascular space and drains into the capillary vessels or meningeal lymphatic tissues. CSF is involved in removing brain waste out of the brain. In this study, we investigated the outfow mechanism of substances in the CSF from the brain. Methods We investigated the movement of CSF by injection of gold colloid conjugates (2, 40, and 200 nm) into the lateral ventricles of mouse fetuses and evaluated the deposition by silver stain with tissue transparency and electron microcopy. Cadaverine was also injected into the lateral ventricle to determine its movement tract. Results The gold particle deposition was mainly observed in the frontal skull base. Electron microscopic study showed that the gold particle deposition was observed on the choroid plexus and ependyma in the lateral ventricle and also red blood cells in the heart and liver. Two-nanometer particles were exclusively observed in the liver. Cadaverine injection study demonstrated that cadaverine was observed at the extracranial frontal skull base, choroid plexus, ependymal surface, and perivascular area in the brain white matter. Conclusion The particles in the CSF were shown to move from the brain to the frontal skull base and also into the blood stream through the choroid plexus in the fetus. The outfow of particles in the CSF may be regulated by molecular size. This new information will contribute to the prevention of brain degeneration due to brain waste deposition. Keywords Cerebrospinal fuid · Outfow · Ventricle · Gold particle Introduction The cerebrospinal fuid (CSF) flls the brain ventricles and the subarachnoid space. It has many important functions that maintain brain homeostasis. It is a physiological fuid that keeps the brain wet, stabilizes intracranial pressure, removes waste products produced by cellular metabolism, and also may provide nutrients to the growing brain [1] [2]. The CSF removes beta-amyloid and tau and contributes to the preven- tion of their accumulation [3–6]. The CSF can be a clinical target for the treatment of Alzheimer’s disease. It is commonly believed that CSF is mainly produced in the choroid plexus [7] and moves into the intracranial subarachnoid space and spinal canal. It then, supposedly, drains into the major dural sinus through arachnoid granulations [7, 8]. The disrup- tion of this system results in hydrocephalus and elevation of * Takuya Akai akai@med.u-toyama.ac.jp 1 Department of Neurosurgery, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, Sugitani, Toyama, Japan 2 Department of Anatomy, Kanazawa Medical University, Uchinada, Ishikawa, Japan 3 Department of Pathology, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, Toyama, Japan 4 Department of Developmental Biology, Faculty of Medicine, Shimane University, Izumo, Shimane, Japan / Published online: 20 July 2021 Child’s Nervous System (2021) 37:3013–3020