A dominant theme in limbic epilepsy research has been the """"""""dentate gate"""""""" hypothesis which states that dentate granule cells of a normal brain limit invasion of CAS and CA1 by seizure activity from entorhinal cortex. In vivo evidence of the """"""""dentate gate"""""""" is based upon 2-deoxyglucose imaging, hippocampal EEG, and field potential recordings of the dentate gyrus (DG) in animal models of seizures. Breakdown of the dentate gate is one mechanism thought to contribute to limbic epileptogenesis, and in vitro evidence from slices of kindled animals suggests increased penetration of excitation through DG into CAS in kindled animals. Recently, however, contrary in vitro evidence from spontaneously seizing animals has suggested that the dentate gate is intact in epileptic animals, and another direct projection from entorhinal cortex, the temporoammonic pathway (which was not studied in kindled slices) is strengthened in epilepsy. Our objective is to assess the various possibilities which lead to a strengthened entorhinal-hippocampal circuit in epilepsy by recording in vivo simultaneously from DG and hippocampal neurons of CAS and CA1 during each stage of kindling, thus eliminating fiber transaction confounds found in vitro and allowing within-animal comparison of the strength of each hippocampal pathway over the course of kindling. Therefore, in my single aim, I will use the powerful new recording technique of multisite single-unit recordings to simultaneously record tens of single units, which can be deciphered as primary neurons or interneurons, and local field potentials within DG, CAS and CA1 during epileptogenesis induced by stimulation of medial entorhinal cortex. This will permit monitoring the sequential recruitment of neurons into seizure activity within each population of neurons during epileptogenesis in the kindling model, thereby determining whether the dentate granule cells do in fact serve as a gate limiting seizure invasion of hippocampus. In sum, our study will directly test the dentate gate hypothesis at the finest resolution of neuronal activity currently available, thus building on years of research in understanding the mechanisms of epileptogenesis. Understanding the mechanisms of limbic epileptogenesis will hopefully lead to more effective treatment and ideally prevention of this disorder.
| Alexander, Georgia M; Rogan, Sarah C; Abbas, Atheir I et al. (2009) Remote control of neuronal activity in transgenic mice expressing evolved G protein-coupled receptors. Neuron 63:27-39 |
