Acute seizures (or status epilepticus, SE) after a severe brain insult often leads to epilepsy and cognitive impairment. Aberrant hippocampal neurogenesis follows the insult but the role of adult-generated neurons in the development of chronic seizures or associated cognitive deficits remains to be determined. Recently, we found ablation of adult neurogenesis prior to acute seizures reduced chronic seizure frequency and normalized epilepsy-associated cognitive deficits. These data helped us formulate a clear objective for this grant proposal: to determine the effect of neurogenesis ablation after acute seizures in chronic seizure generation and epilepsy-associated memory function. Our central hypothesis is adult neurogenesis plays a key role in chronic seizure development and associated memory impairment, and our preliminary results suggest that targeting aberrant hippocampal neurogenesis may reduce recurrent seizures and restore cognitive function following a pro-epileptic brain insult. We will test this hypothesis in 3 specific aims: 1) To defie the therapeutic window of targeting adult neurogenesis to prevent epilepsy and associated cognitive deficits, 2) To evaluate the long-term effects of aberrant neurogenesis in preventing epilepsy, and 3) To identify molecules to target aberrant neurogenesis through studies on NeuroD.
Aims 1 and 2 will utilize a Nestin-?-HSV-thymidine kinase transgenic mouse to genetically ablate newborn neurons.
Aim 1 will also use an Ascl1-CreERT2; inducible DT-A model to ablate neurogenesis.
Aim 3 will use a NeuroD conditional knockout mouse. In all 3 Aims, we will perform continuous video-EEG recording to measure chronic seizure frequency and duration.
In Aims 1 and 2, novel location, novel object, and context-dependent fear conditioning tests will be performed to measure memory function. The conceptual framework and approach is innovative because we will apply state-of-the-art genetic and knockout mouse techniques to a mouse model of temporal lobe epilepsy and dissect underlying cellular- level mechanisms of SE-dependent neurogenesis. As our long-term goal is to understand the molecular mechanisms important for how aberrant neurogenesis drives chronic epilepsy, the proposed work is disease- relevant and highly significant. It will advance and expand our basic understanding of seizure activity- dependent molecular networks regulating neural stem cell proliferation, differentiation, survival and maturation of newborn neurons, which will advance our understanding of neurogenesis in both basal and pathological states. The proposed study is relevant to NIH's mission as it will allow us to gain fundamental insight regarding the fundamental underpinnings of epilepsy and associated comorbidities as well as acquiring knowledge towards new avenues for treating neurological and psychiatric disorders.
Disease, degeneration or traumatic injury of the nervous system are among the greatest public health concerns in the United States and are generally considered irreparable, often causing catastrophic damage to the functional capacity of the individual. Now, however, characterization of neural stem cells residing within specific germinal centers of the brain and in cell culture raises hope that functional regeneration of nervous tissue may be feasible, if we learn to exploit adult neurogenesis for clinical benefit. The research proposal will lead to improved understanding of neural stem cell biology, especially aberrant hippocampal neurogenesis, possibly leading to the development of new drugs for reducing chronic seizures after a severe brain insult.
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