Under pressure: Cerebrospinal fluid contribution to the physiological homeostasis of the eye

Abstract

The cerebrospinal fluid (CSF) is a waterly, colorless fluid contained within the brain ventricles and the cranial and spinal subarachnoid spaces. CSF physiological functions range from hydromechanical protection of the central nervous system (CNS) to CNS modulation of developmental processes and regulation of interstitial fluid homeostasis. Optic nerve (ON) is surrounded by CSF circulating in the subarachnoid spaces and is exposed to both CSF (CSFP) and intra ocular (IOP) pressures, which converge at the lamina cribrosa (LC) as two opposite forces. The trans–lamina cribrosa pressure gradient (TLPG) is defined as IOP - CSFP and its alterations (due either to an elevation in IOP or a reduction in ICP) could result in structural damaging of the ON, including glaucomatous changes.

The purpose of this review is to update the readers on the CSF contribution in controlling the functions/dysfunctions of ON by regulating homeostasis at LC. We also highlight emerging parallelisms regarding the expression of cilia-related genes in the regulation of common functions of body fluids in both brain and eye structures.

Introduction

CSF is the nutrient-rich fluid that bathes the brain and spinal cord. It is continuously secreted into the cerebral ventricles by the choroid plexus (CP), a layer of surrounding a core of capillaries, and it is absorbed into the venous system. CSF plays an essential role in the homeostasis of the interstitial fluid of the brain parenchyma and the regulation of neuronal function [[1], [2], [3]]. Indeed, CSF composition is tightly controlled and includes amino acids, vitamins, minerals, ions, growth factors and signalling molecules that are kept at very specific concentrations depending on the developmental stage [4]. Additionally, CSF helps to cushion the central nervous system from mechanical injury. Alterations in CSF dynamics and composition are responsible for the major alterations of cerebral homeostasis and physiology observed in hydrocephalus and dementia disorders [5].

A first mention of a mysterious fluid inside the brain is found in the writings of the ancient Egyptians (1700 BCE) [6]. In Greece, Hippocrates (129–219 AD) also reported the presence of “water inside the head” in hydrocephalus subjects, while Galen of Pergamon (129–200/216 CE) described a “vaporous and smoky” secretion at the base of the brain, arising from the blood vessels as a “vital spirit”. The succession of events orchestrating the development of brain ventricular cavity-CSF system is quite uniform across mammalian species. The CSF formation rate appears to increase gradually during ontogenesis, supporting the functional importance of the CSF in regulating the development of CNS [7]. The CSF formation rate has been measured, for example, in turtles (1.4 μl/min), rats (2.2 μl/min), rabbits (8–11 μl/min), cats (14–21 μl/min), monkeys (19–35 μl/min), and goats (160 μl/min μl/min) [8,9]. In rats and many other species the gradual increase of CSF formation during postnatal development correlates with postnatal morphological and functional maturation of choroidal epithelium [10]. However, the ontogeny and phylogeny of the “vital spirit” around which the vertebrate brain is organised is not fully understood yet. Beyond vertebrates, the CSF system is hypothesized to appear in the deuterostome lineage as a way to maintain the chemical environment required for the functioning of CNS cells, including the neuroendocrine pathways. Earlier in the phylum Chordata, the cephalochordate amphioxus includes a larval stage in which the CNS is open through the neuropore, thus allowing seawater to enter the ventricular lumen. However, after metamorphosis, the anterior neuropore closes and the brain becomes a closed system, with a proper CSF regulating brain development and homeostasis [11]. Strikingly, one main innovation at early stages of vertebrate origins was probably a heterochronic switch to an early closure of the neuropore during embryogenesis (and also, the secretion of an embryonic-eCSF distinct from the adult CSF), which translated into an early isolation of the brain cavities from the surrounding external media, hence enabling a higher level of internal control and regulation (Fig. 1; reviewed in [12] and [13]).

The ON develops from the optic vesicle, an outpocketing of the forebrain, and can be considered part of the CNS [14]. As a CNS structure, the ON is myelinated by oligodendrocytes, ensheathed in the cranial meningeal layers and surrounded by CSF circulating within the subarachnoid space [14]. Recently, many studies have demonstrated that an imbalanced pressure exercised by CSFP induce structural damage of the ON [15,16]. CSFP, together with IOP, create a pressure gradient at the LC, a specialized region at the optic nerve head (ONH). TLPG imbalance could be a major determinant for the pathophysiology of several eye diseases, such as glaucoma.

In this review, we aim to describe what is known about CSF physiological contribution to maintain LC homeostasis and its potential as a pathophysiologic factor in ONH diseases. We highlight the CSF theory of glaucoma, a collection of diseases characterized by progressive degeneration of the ON cells that represent a leading cause of irreversible blindness worldwide. Finally, we highlight emerging parallelisms in the expression of genes controlling the function/dysfunction of body fluids circulating in both brain and neurosensory organs.