NMDA receptor dependence of kindling and mossy fiber sprouting: evidence that the NMDA receptor regulates patterning of hippocampal circuits in the adult brain.

The NMDA receptor plays an important role in patterning neural connectivity in the developing brain. In the adult brain, repeated kindling stimulation of limbic pathways increases the NMDA-dependent component of synaptic transmission in granule cells of the dentate gyrus (DG) and also induces sprouting of the mossy fiber axons of granule cells that reorganizes synaptic connections in the DG. Because the NMDA antagonist MK801 impedes the progression of kindling, it was of interest to determine whether MK801 also modified mossy fiber sprouting. Low doses of MK801, which had no antiseizure effect, impaired the progression of kindling and development of mossy fiber sprouting during the initial and also more advanced stages of kindling. These observations demonstrate that the NMDA receptor is a component of a molecular pathway that influences the progression of kindling and mossy fiber sprouting and suggest that NMDA-dependent gene expression may play a role in the development of long-term structural and functional alterations induced by seizures in hippocampal circuitry. The NMDA receptor appears to play a continuing role in modifying the organization and patterns of connectivity in hippocampal circuits of the adult brain.