The dentate gyrus serves as a critical regulatory entry point to the hippocampus, translating the highly active coding language of medial entorhinal cortical neurons to the distinct, sparse encoding that is characteristic of hippocampal function. This dentate gyrus-mediated translation is vital to many aspects of information processing in the CNS. The underlying circuit mechanisms responsible for this activity level transformation within the dentate gyrus are largely unknown, but local circuit inhibitory neurons are hypothesized to play an important role. The dentate gyrus also functions to regulate pathological activation of the limbic system, restricting relay of aberrant activity from the entorhinal cortex to the hippocampus. Loss of this filter or gating function could contribute to the generation of seizures, the hallmark of epilepsy. In this proposal, we will utilize state of the art imaging, patch clamp, chemogenetic, and transgenic techniques to test the hypotheses that that the sparse firing properties characteristic of dentate granule cells are generated within the local circuit, and that degradation in these mechanisms contributes both to seizure predisposition and cognitive comorbidities characterizing epilepsy. We propose to determine the cellular properties that mediate dentate granule cell activation, learn the identity of interneurons responsible for the control of dentate granule cell activation, study the mechanisms responsible for degradation in granule cell sparse firing in epileptic animals, and finally, restore normal cognitive function in animals with epilepsy using chemogenetic manipulation of granule cell firing levels. We know little about the mechanisms mediating the firing properties of neurons in the hippocampal dentate gyrus responsible for information coding, and even less about how epilepsy may erode this critical aspect of the cognitive functions emerging from the hippocampus. In addition to seizures, patients with epilepsy exhibit severe deficits in learning and memory. Understanding how epilepsy development alters circuit properties within the limbic system may be important not only in targeting new therapies for seizure amelioration, but also in developing new treatments to reduce comorbid conditions accompanying epilepsy development.
Despite the fact that relay of information through the dentate gyrus is a vital component contributing to cognitive functions of the hippocampus, we know little about its activation properties, either in normal, healthy individuals or in patients with epilepsy. This proposal will examine the activation properties of the principal cells of the dentate gyrus, granule cells, using advanced imaging, patch clamp recording, chemogenetic, and transgenic techniques, focusing on the mechanism determining how individual neurons within the dentate gyrus make the decision to activate, both in normal animals, and in animal models of epilepsy. Insight derived from these studies should facilitate the development of better, more effective treatments for the associated co-morbidities accompanying epilepsy development.
