The Role of NeuroD1 in Physiological and Pathological Neurogenesis

Neurogenesis in the adult brain is a complex and highly regulated process. Under normal physiological conditions neurogenesis in the hippocampal subgranular zone (SGZ) is important for learning, memory, and mood regulation. What is not well understood, however, is whether in certain disease contexts, like epilepsy, aberrant neurogenesis can contribute to the progression of spontaneous reoccurring seizures (SRS) and associated memory decline. In this work, I present evidence that aberrant hippocampal neurogenesis is causative in the perpetuation of SRS. In an effort to target a select stage of adult neurogenesis I identified the bHLH transcription factor NeuroD1, known to be important in adult neurogenesis, as being strongly upregulated after status epilepticus (SE). Additionally, I show expression of NeuroD1 in aberrant ectopically localized granule cells suggesting a potential role for this transcription factor in the progression of epilepsy. NeuroD1 conditional knockout (cKO) in progenitor cells of the hippocampus may be sufficient to reduce the number of immature and mature neurons amongst the labeled population, however the total number of immature and mature neurons was not significantly changed aside from the immature neurons ectopically localized to the hilus. Consistent with this, the total SRS was unchanged in the NeuroD1 cKO. Transdifferentiation, or the direct inter-lineage conversion of adult somatic cells is a powerful tool with the potential to be used in neuronal replacement strategies in certain neurological disorders or CNS injuries. Transdifferentiation of reactive astrocytes into glutamatergic neurons via retroviral targeting in the cortex can be accomplished by overexpression of the transcription factor NeuroD1. However, what is not well understood is whether the state of reactive gliosis is necessary to "prime" these cells for the transdifferentiation process. In this work I present evidence to suggest that overexpression of NeuroD1 in the absence of reactive gliosis is capable of astrocyte to neuron transdifferentiation, however the total number of converted cells is vastly lower than what was previously published, suggesting that reactive gliosis does indeed enhance and facilitate the conversion process.