Plasticity of Dentate Granule Cell Mossy Fiber Synapses: A Putative Mechanism of Limbic Epileptogenesis

The epilepsies constitute the third most common serious neurological disorder. Among the more than 40 different types of epilepsy, limbic epilepsy is the single most common and devastating form. Antiseizure drugs provide symptomatic relief, in that they suppress seizures, yet limbic seizures persist in 30–40% of patients and unwanted effects of drugs are common. No disease modifying therapies are available. Insight into the underlying mechanisms in cellular and molecular terms may provide novel molecular targets for developing preventive or curative therapies. The availability of animal models of limbic epilepsy has provided an opportunity to elucidate the mechanisms. Plasticity of excitatory synapses of principal neurons has been advanced as one cellular mechanism underlying the hyperexcitability of the epileptic brain (14). Among the diverse populations of neurons within the limbic system, the dentate granule cells of the hippocampal formation have emerged as a rate limiting step in limbic seizure propagation. Moreover, this “gatekeeper” function of the granule cells is compromised in some models of limbic epilepsy. This chapter reviews evidence implicating the granule cells as gatekeepers in a normal brain, as well as, evidence of compromise of the gatekeeper function in an epilepsy model. We further discuss the functional connectivity of the granule cells with their principal cell targets in CA3, the seizure prone CA3 pyramidal cells. We propose that plasticity of dentate granule cell mossy fiber synapses is a putative mechanism of limbic epileptogenesis. 1 Duke University, Department of Neurobiology, Durham, NC 27710, USA, [email protected] 2 Duke University, Department of Neurobiology, Durham, NC 27710, USA, [email protected] 3 Duke University, Department of Neurobiology, Durham, NC 27710, USA, [email protected]