The role of brain extracellular proteins in neuroplasticity and learning

Abstract

Double labeling studies of the pattern of protein synthesis in goldfish and mouse brain identified a class of glycoproteins (the ependymins) whose turnover rate was enhanced after training. A variety of control experiments indicated that these macromolecules have an important role in the molecular and cell biology of learning. Antisera to the ependymins when injected into the brains of trained goldfish cause amnesia of a newly acquired behavior. Isolation and localization studies by immunocytochemical methods indicate that the ependymins are released into the brain extracellular fluid by a class of neurosecretory cells. In mammalian brain ependymin-containing cells are highly concentrated in the limibic system. The ependymins are constituted from two disulfide-linked acidic polypeptide chains (M.W.37K and 31K). They contain at least 5% covalently bound carbohydrate per chain with mannose, galactose, N-acetylglucosamine and N-acetylneuraminic acid as the predominant components. The highly soluble ependymins can rapidly polymerize to form an insoluble fibrous matrix if calcium is removed from solution by the addition of a Ca2+-chelating agent or dialysis. The self-aggregation property of the ependymins can be triggered by the depletion of Ca2+ from the extracellular space. Studies of the kinetics of the aggregation phenomenon by measurements of turbidity changes indicate that the process can be terminated but not reversed by restoring Ca2+ to its normal CSF level. Immunohistochemical studies of the brains of trained goldfish show the presence of punctate statining sites in the perimeter of certain cells located in specific brain regions. This suggests that ependymin aggregation might occur in vivo during learning. A molecular hypothesis relating the aggregation properties of the ependymins to neuroplasticity and learning is proposed.

Ependymin as a substrate for outgrowth of axons from cultured explants of goldfish retina

“…This antibody also prevents memory consolidation after operant vestibulomotor training (Schmidt, 1987) and classical shock-avoidance conditioning (Piront and R. . Shashoua, 1985), but soluble ependymin undoubtedly remained and plated onto the glass as well.…”

“…Learning triggers protein synthesis (Shashoua, 1976(Shashoua, , 1985Schmidt, 1987Schmidt, , 1989Shashoua and Hesse, 1989;Duffy, Teyler, and Shashoua, 1981;Fazeli, Errington, Dolphin, and Bliss, 1988), and memory consolidation depends upon protein synthesis (Rexner et al, 1963;Goelet et al, 1986). Ependymin is one of the proteins synthesized (Shashoua, 1976;Fazeli et al, 1988).…”

“…development where similar synaptic changes occur. One such protein, ependymin (Ep), has been implicated in the consolidation of memory in goldfish and mice (Shashoua, 1985;Schmidt, 1986) and in activity-driven retinotopic sharpening of the regenerating retinotectal projection of goldfish (Schmidt and Shashoua, 1988).…”

“…Ependymin has been localized by immunohistochemical staining within the ependymal glia (Benowitz and Shashoua, 1977;Schmidt and Shashoua, 1988), the leptomeninx (Schmidt, 1983) and some neurons (Schmidt et aI., 1986(Schmidt et aI., , 1990, and is continually secreted as a disulfide-linked dimer of two polypeptide chains (37 and 31 kD) into the brain extracellular fluid (ECF) (Schmidt and Shashoua, 1981;Shashoua, 1985). It was first identified by double-labelling methods as a glyco-40 First publ.…”

“…Because sustained activity at convergent synapses can transiently lower local calcium concentrations by as much as 70% (Krnjevic, Morris, and Reiffenstein, 1982;Marciani, Louvel, and Heinemann, 1982;Morris, Ropert, and Shashoua, 1988), the resulting deposition of polymerized ependymin into a matrix (Shashoua and Hesse, 1985) could play a role in promoting increased growth or elaboration at the sites of the participating synapses (Shashoua, 1985).…”