A role for glial cells in activity-dependent central nervous plasticity? Review and hypothesis.

Activity-dependent plasticity relies on changes in neuronal transmission that are controlled by coincidence or noncoincidence of presynaptic and postsynaptic activity. These changes may rely on modulation of neural transmission or on structural changes in neuronal circuitry. The present overview summarizes experimental data that support the involvement of glial cells in central nervous activity-dependent plasticity. A role for glial cells in plastic changes of synaptic transmission may be based on modulation of transmitter uptake or on regulation of the extracellular ion composition. Both mechanisms can be initiated via neuronal-glial information transfer by potassium ions, transmitters, or other diffusible factor originating from active neurons. In addition, the importance of changes in neuronal circuitry in many model systems of activity-dependent plasticity is summarized. Structural changes in neuronal connectivity can be influenced or mediated by glial cells via release of growth or growth permissive factors on neuronal activation, and by active displacement and subsequent elimination of axonal boutons. A unifying hypothesis that integrates these possibilities into a model of activity-dependent plasticity is proposed. In this model glial cells interact with neurons to establish plastic changes; while glial cells have a global effect on plasticity, neuronal mechanisms underlie the induction and local specificity of the plastic change. The proposed hypothesis not only explains conventional findings on activity-dependent plastic changes, but offers an intriguing possibility to explain several paradoxical findings from studies on CNS plasticity that are not yet fully understood. Although the accumulated data seem to support the proposed role for glial cells in plasticity, it has to be emphasized that several steps in the proposed cascades of events require further detailed investigation, and several "missing links" have to be addressed by experimental work. Because of the increasing evidence for glial heterogeneity (for review see Wilkin et al., 1990) it seems to be of great importance to relate findings on glial populations to the developmental stage and topographical origin of the studied cells. The present overview is intended to serve as a guideline for future studies and to expand the view of "neuro" physiologists interested in activity-dependent plasticity. Key questions that have to be addressed relate to the mechanisms of release of growth and growth-permissive factors from glial cells and neuronal-glial information transfer. It is said that every complex problem has a simple, logical, wrong solution. Future studies will reveal the contribution of the proposed simple and logical solution to the understanding of central nervous plasticity.