In the mammalian adult brain, there are two regions where stem cells continuously give rise to new neurons, a process termed adult neurogenesis: the subventricular zone and the subgranular zone of the dentate gyrus (DG). In the DG, adult-born neurons normally become granule cells (GCs), the principal cell type. It has been suggested that adult neurogenesis in the DG is required for normal cognitive functions, and to stabilize mood. It also has been suggested that adult neurogenesis plays a role in temporal lobe epilepsy (TLE) where seizures involve the DG. However, it is not yet clear how adult-born granule cells (GCs) influence the function of the DG and how this might influence seizures in TLE. Our preliminary results indicate that newborn neurons influence activity in the DG by modulating local network inhibition via the connections young neurons make with GABAergic interneurons. Specifically, preliminary data show that inhibition (assessed by extracellular field recordings) is reduced in mice lacking adult neurogenesis following focal X-ray irradiation or selective ablation of precursors in an adult mouse. Based on our preliminary results, we hypothesize that young adult-born GCs inhibit the activity of mature GCs via the activation of local inhibitory interneurons. Our preliminary data also suggest, remarkably, that adult-born neurons reduce the effects of the convulsant kainic acid. These effects are significant because they would allow adult-born neurons to regulate the role of the DG as a "gate" to entorhinal cortical input, where it is proposed that the DG prevents excessive activation of hippocampal neurons. This gating of cortical input appears to be important so that fine differences in patterns of input can be discriminated, a function called pattern separation. In TLE, where it has been suggested that this gate weakens, the preliminary data suggest that adult neurogenesis influences seizures. However, it is hard to predict how seizures will be influenced in the epilepti brain because many GCs that are born in animal models of epilepsy are abnormal and appear to facilitate seizures rather than inhibit them. To address these questions we will 1) determine whether the pathway from the entorhinal cortex that activates hippocampus via the DG (entorhinal-DG-CA3) is normally inhibited by adult-born GCs using physiological methods in hippocampal slices, 2) test selective optogenetic activation or inhibition of young GCs to determine if there is a preferential effect on the activity of interneurons, consistent with preliminary data, and 3) test the hypothesis that modulation of adult-born GCs will affect acute and chronic seizures in an animal model of TLE. We predict that the results will lead to a paradigm shift because they will show that adult neurogenesis has diverse roles: in the normal brain, adult-born neurons of the DG are inhibitory and protective, whereas in TLE, abnormalities that arise in adult-born neurons contribute to the pathophysiology of the disease, and facilitate seizures.
Adult neurogenesis, the generation of new neurons in the adult brain, occurs in only two locations in the brain, and one is the dentate gyrus. The idea that neurons can be generated in the dentate gyrus in adult life has gained widespread interest among neuroscientists and clinicians, but the functional roles of the adult-born neurons are still unclear. We hypothesize that adult-born neurons have diverse roles: under normal conditions, our preliminary data suggest that adult-born neurons have a net effect that is inhibitory and protective;in epilepsy, however, adult-born neurons can become abnormal and create recurrent excitatory circuits, which we suggest contribute to chronic seizures.
|Mukherjee, Shradha; Brulet, Rebecca; Zhang, Ling et al. (2016) REST regulation of gene networks in adult neural stem cells. Nat Commun 7:13360|
|Kam, Korey; Duffy, Ãine M; Moretto, Jillian et al. (2016) Interictal spikes during sleep are an early defect in the Tg2576 mouse model of Î²-amyloid neuropathology. Sci Rep 6:20119|
|Scharfman, Helen E; Myers, Catherine E (2016) Corruption of the dentate gyrus by "dominant" granule cells: Implications for dentate gyrus function in health and disease. Neurobiol Learn Mem 129:69-82|
|Drew, Liam J; Kheirbek, Mazen A; Luna, Victor M et al. (2016) Activation of local inhibitory circuits in the dentate gyrus by adult-born neurons. Hippocampus 26:763-78|
|Wu, Melody V; Sahay, Amar; Duman, Ronald S et al. (2015) Functional differentiation of adult-born neurons along the septotemporal axis of the dentate gyrus. Cold Spring Harb Perspect Biol 7:a018978|
|Cho, Kyung-Ok; Lybrand, Zane R; Ito, Naoki et al. (2015) Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline. Nat Commun 6:6606|
|Miller, Bradley R; Hen, RenÃ© (2015) The current state of the neurogenic theory of depression and anxiety. Curr Opin Neurobiol 30:51-8|
|Iyengar, Sloka S; LaFrancois, John J; Friedman, Daniel et al. (2015) Suppression of adult neurogenesis increases the acute effects of kainic acid. Exp Neurol 264:135-49|
|Fisher, Robert S; Scharfman, Helen E; deCurtis, Marco (2014) How can we identify ictal and interictal abnormal activity? Adv Exp Med Biol 813:3-23|
|Jiang, Yindi; Hsieh, Jenny (2014) HDAC3 controls gap 2/mitosis progression in adult neural stem/progenitor cells by regulating CDK1 levels. Proc Natl Acad Sci U S A 111:13541-6|
Showing the most recent 10 out of 14 publications