Impact of intracellular chloride-dependent modulation of radial glia-like stem cells on hippocampal neurogenesis and the associated cognitive function in the aging brain

• Applicant: Dr. Silke Keiner
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases ; Molecular Biology and Physiology of Neurons and Glial Cells ; Molecular and Cellular Neurology and Neuropathology
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 387160330

Throughout the lifespan of rodents, primates and humans, radial glia-like stem cells (RGLs) in the hippocampal dentate gyrus have the capacity to produce new neurons. Previous studies have shown that hippocampal neurogenesis is critically involved in learning, memory and emotional behaviour. The inhibitory neurotransmitter GABA, acting via the GABAA receptor, regulates multiple stages of adult neurogenesis, including neural progenitor cell proliferation and migration, neuronal maturation, synaptic integration and survival. Previous studies have investigated the impact of GABAA signalling on proliferation and differentiation of neural stem and progenitor cells, as well as its influence on the control of network activity of hippocampal stem cells. However, the role of NKCC1- and KCC2-modulated intracellular chloride levels in the age-dependent activity of RGLs, neural stem cell self-renewal, differentiation and survival in the dentate gyrus remains unknown. Several studies showed that adult neurogenesis is severely impaired in the aged brain and is characterised by a continuous decrease in the number of RGLs. This decrease has been associated with the age-related cognitive decline and reduced regenerative capacity of the aged brain. Our preliminary data show that NKCC1 knockout in RGLs significantly increases the number of RGLs, mature neurons and astrocytes in the aged brain. The aim of the present proposal is to analyse new mechanisms of RGL activation and adult neurogenesis in the hippocampus associated with the modulation of intracellular chloride levels. Therefore, we will utilise novel transgenic mouse models for specific NKCC1 knockout (NestinCreERT2/NKCC1fl/fl/tdTomato mice) and KCC2 overexpression (Nestin-rtTA/tetOKCC2/tdTomato mice) in RGLs in the hippocampal dentate gyrus. We will determine the impact of intracellular chloride level modulation on neurogenesis in the hippocampal dentate gyrus and on cognitive function in the aging brain. In the first part of the proposal, we will determine the level of self-renewal and the fate of RGLs on the single-cell (clonal analysis) and population levels at different ages (Project A). Further, we will analyse the functional impact of changing RGL activation with increasing age, using different cognitive behavioural tests (Project B). Our study will contribute to the understanding of underlying mechanisms of RGL activation and their involvement in the ag

• DFG Programme: Research Grants