Synaptic Integration of Hippocampal Neurons Generated in the Adult Brain: Influence of a Pathological Environment

Abstract: The adult brain constantly produces new neurons from endogenous neural progenitor cells located in at least two regions, the subgranular zone (SGZ) in dentate gyrus of the hippocampus, and the subventricular zone (SVZ). Major efforts are underway to discover the functional significance of new neurons in the adult brain. Several studies have indicated a relationship exists between newborn hippocampal neurons and learning and memory, suggesting that the new neurons have a physiological role within the established circuitry. Individual newborn hippocampal neurons develop into functional dentate granule cells and integrate normally into the hippocampal circuitry. They develop electrophysiological properties that are indistinguishable from the granule cells that were formed during early development. Adult neurogenesis may provide the possibility for neuronal replacement therapy. Several brain pathologies have been shown increase or decrease the magnitude of neurogenesis in the dentate gyrus. However, we do not know how the new neurons function when they are born in a pathological environment. This information is crucial for potential neuronal repair strategies utilizing endogenous neural progenitor cells. In this thesis, we used electrophysiological techniques to study the functional integration of new neurons born in a pathological environment. In the first study, we used an animal model of temporal lobe epilepsy, status epilepticus (SE), characterized by abnormal seizure activity, cell death and inflammation. In the second study we caused inflammation by intrahippocampal administration of lipopolysaccharide (LPS), which induced a strong inflammatory response but no seizure activity or cell death. After the insult, the new cells were labeled with a retrovirus tagged with green fluorescent protein (GFP), which incorporates into dividing cells and the protein is expressed throughout the cell body and processes.The new cells were identified in acute brain slices based on their GFP expression and subjected whole-cell patch-clamp recordings. We found that after SE the synaptic properties of the newborn neurons were consistent with enhanced inhibition and reduced excitation, indicating they may act to attenuate the hyperexcitability caused by epilepsy. After the LPS-induced inflammation, the new neurons also received enhanced inhibitory input. Our findings indicate that the environment in which new neurons are born dramatically influences their synaptic integration into the circuitry. The overall functional significance is not known, and further studies are warranted in order to understand underlying mechanisms. Such investigations may lead to potential neuronal replacement strategies harnessing endogenous neural progenitor cells.