Developmental Analysis of Hippocampal Mossy Fiber Mutant Mouse with Inherited Spike-Wave Seizures Outgrowth in a

Neural firing patterns are an essential determinant of normal axon terminal growth and synaptic connectivity in developing afferent pathways, but the trophic role of synchronous activity in associative neural networks is less well defined. We examined the ontogeny of inherited synchronous hippocampal network discharges and mossy fiber innervation patterns at sequential stages of development in the stargazer (sfg) mutant, a single-locus mouse mutation expressing generalized spike-wave epilepsy. Brief bursts of G/set repetitive discharges arise spontaneously on postnatal days 17-l 6 and persistently activate neocortical and hippocampal networks throughout adulthood. We found a striking pattern of mossy fiber recurrent axon collateral sprouting in the inner molecular layer of dentate gyrus in the adult sfg hippocampus. Sprouting is not apparent until 4-6 weeks following seizure onset, but then steadily intensifies with continued synchronous activation. In the adult mutant, axon outgrowth is accompanied by a mild selective loss of hilar interneurons without gliosis. These data indicate that hypersynchronous stimulation during late postnatal brain development is linked, following a prolonged latent period, to significant fiber outgrowth and synaptic reorganization within the hippocampal formation. Since the pattern of synchronous activation in the sfg mutant strongly resembles that seen in human spike-wave absence epilepsy, the synaptic plasticity described in this model has important implications for normal brain development in this common disorder. [