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Development of GABAergic Inputs to Adult Born Dentate Granule Neurons in the Mouse Hippocampus

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New neurons are continuously produced in the subgranular zone of the dentate gyrus of the hippocampus throughout life. These newborn dentate granule cells (DGCs) undergo a stereotyped process of morphological and functional maturation during the first few weeks after differentiation that recapitulates some aspects of postnatal neuronal development. The inhibitory neurotransmitter GABA is critical for survival, morphological development, and functional maturation of adult-born DGCs (abDGCs). While the importance of GABAergic synaptogenesis to abDGCs survival and development has been well characterized, little is known about the precise pattern of connectivity between abDGCs and local interneurons, the main source of GABA inputs onto abDGCs. This process of maturation and functional integration of abDGCs can be influenced by an array of intrinsic and extrinsic factors ranging from disease to experience. In this dissertation, I will discuss the development of GABAergic inputs to developing abDGCs and assess whether this process is differentially regulated in a model of a neurodevelopmental disorder as well as by experience. In Chapter 2, I discuss the role of the gene disrupted in Fragile X syndrome Fmr1 in the functional maturation of abDGCs. Fragile X mental retardation protein (FMRP) has been shown to play a role in adult neurogenesis and behaviors that rely on this process, however it is not known whether the functional synaptic maturation and integration of abDGCs into hippocampal circuits is affected in Fmr1 knockout (KO) mice. These studies systematically characterized the functional development of abDGCs during the first four weeks after differentiation and demonstrate that the maturation of GABAergic synaptic inputs to these neurons is not grossly affected by the loss of FMRP. In Chapter 3, I characterize the development of inputs from two morphologically and chemically distinct populations of interneurons in the dentate gyrus. The dentate gyrus contains a diverse population of interneurons, but the present study focused on somatostatin (SST) expressing and parvalbumin (PV) expressing interneurons because these are among the most well-studied interneurons in the dentate gyrus, they can be identified by distinct chemical markers allowing us to genetically label them, and their axons project to distinct regions of the dentate where they innervate separate cellular compartments of mature DGCs. PV interneurons are the most well-characterized inputs to abDGCs, however they have not been studied beyond the first week of abDGC development. I also determined the effects of voluntary wheel running of mice on functional connectivity between abDGCs and these specific populations of interneurons. I show that the time course of development of inputs from PV and SST interneurons is likely explained by the organization of interneuron projections within the dentate. Young abDGCs first receive synaptic input from PV interneurons in the granule cell layer, as these cells mature and extend increasingly complex dendrites into the molecular layer where they receive synaptic inputs from SST interneurons. I also show that voluntary wheel running increases input from both PV and SST interneurons, but with different time courses. Understanding the process of integration of abDGCs into the existing hippocampal circuitry will contribute to our understanding of the role of adult neurogenesis in information processing and disease.

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