Neuropeptide signaling and hydrocephalus: SCO with the flow

Abstract

Congenital hydrocephalus affects 0.1-0.3% of live births, with a high mortality rate (approximately 50%) in the absence of surgical intervention. Although the insertion of shunts alleviates the symptoms of the majority of congenital cases, the molecular basis of hydrocephalus and the mechanisms of cerebrospinal fluid (CSF) circulation remain largely unknown. Two important players are the subcommissural organ/Reissner's fiber (SCO/RF) complex and the ventricular ependymal (vel) cells that together facilitate the flow of the CSF through the narrow canals of the ventricular system. In this issue of the JCI, Lang et al. demonstrate that overexpression of the pituitary adenylate cyclase-activating polypeptide (PACAP) type I (PAC1) receptor gene results in abnormal development of the SCO and vel cells, leading to congenital hydrocephalus (see the related article beginning on page 1924). The ligand for the PAC1 receptor is the neuropeptide PACAP, which uncovers what the authors believe to be a novel role for this signaling cascade in the regulation of CSF circulation.

Figure 1. CSF flow and the SCO.

CSF is secreted from the choroid plexus and travels through the ventricular system in a rostrocaudal direction from the lateral ventricles to the third ventricle via the foramen of Munro, then through the Sylvian aqueduct to the fourth ventricle, and finally into the cisterna magna of the subarachnoid space and the central canal of the spinal cord. CSF fluid is removed through the arachnoid villi into the venous circulation.

Figure 2. Schematic diagram modeling flow through the Sylvian aqueduct in WT and PAC1 receptor transgenic mice.

(A) In WT mice, ependymal cells from the SCO secrete glycoproteins that form RF and help maintain laminar flow of the CSF through the aqueduct. Cilia on the vel cells also promote CSF flow. (B) In transgenic animals, there are fewer SCO cells, which may result in absent or disorganized RF but not stenosis of the aqueduct. In addition, shorter, inefficient cilia are present on the vel cells. Together, these defects likely result in turbulent CSF flow at the entrance (curved arrows) and reduced flow within (dashed arrows) the cerebral aqueduct, thereby promoting hydrocephalus.

Figure 3. Potential mechanisms of increased PAC1 receptor signaling.

Schematic representation of PACAP/PAC1 receptor signaling through the PKA and PKC pathways. AC, adenylyl cyclase; DG, diacylglycerol; IP₃, inositol triphosphate; MAPKK, MAPK kinase; MAPKKK, MAPKK kinase.