Neural plasticity in cerebellar cultures.

Cerebellar granule cells and oligodendrocytes are destroyed and astrocytes are functionally compromised by exposure of organotypic cerebellar cultures derived from newborn mice to cytosine arabinoside for the first 5 days in vitro. Consequently, myelin does not form and Purkinje cells survive in increased numbers, but without astrocytic ensheathment. In the absence of glial sheaths, Purkinje cells have altered membrane properties and reduced input resistance. Their inhibitory recurrent axon collaterals sprout enormously and hyperinnervate the unensheathed somata of other Purkinje cells and form heterotypical synapses with Purkinje cell dendritic spines normally occupied by homotypical excitatory parallel fiber (granule cell axon) terminals. This reorganization of the cortical circuitry, in which recurrent axon collaterals are the dominant inhibitory elements, allows retention of some inhibition in the absence of parallel fiber excitation of the inhibitory interneurons. In the absence of neuronal activity, the full complement of inhibitory synapses is not developed and the cultures exhibit sustained cortical hyperactivity after recovery from the blockade. If granule cells and glia are replaced, a second round of reorganization ensues, in the direction of restoration of the normal cortical circuitry. The cultures are myelinated and the number of recurrent axon collaterals is reduced. Astrocytes ensheath Purkinje cell somata and strip excess axosomatic synapses, as well as eliminate some of the heterotypical synapses in the cortical neuropil. Parallel fibers synapse with already present Purkinje cell dendritic spines and with newly proliferated spines, the latter induced by an astrocyte secreted factor. As homotypical synapses develop and heterotypical synapses decline, Purkinje cells undergo apoptosis and their population is reduced to control levels. With the restoration of parallel fiber excitation, recurrent axon collaterals are no longer the dominant cortical inhibitory elements. If neuronal activity is blocked as the granule cells and glia are replaced, there is incomplete formation of inhibitory synapses, and cortical discharges are hyperactive after recovery from activity blockade.