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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS081203-01A1
Application #
8598169
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Whittemore, Vicky R
Project Start
2013-07-01
Project End
2018-04-30
Budget Start
2013-07-01
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$375,406
Indirect Cost
$137,322
Name
Nathan Kline Institute for Psychiatric Research
Department
Type
DUNS #
167204762
City
Orangeburg
State
NY
Country
United States
Zip Code
10962
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