The birth of new neurons (called neurogenesis) in the adult hippocampus is critical for learning and memory and disruption of this process is associated with human neurological disorders such as Alzheimer?s disease. Rates of adult hippocampal neurogenesis (AHN) are tightly linked with changes in physiological activity. Activities such as enhanced exercise or learning as well as pathophysiological changes such as epilepsy, profoundly alter AHN. Knowing how ANH neurogenesis regulates neuronal circuitry is therefore important for understanding its overall impact on brain physiology. Central to this issue is understanding how newborn neurons in adult brain achieve long-term integration. Understand the molecular and cellular mechanisms regulating synaptic integration in AHN could lead to selective pharmacological targets for functional improvement during pathological conditions or in aging where levels of adult neurogenesis are dramatically decreased. Neuronal progenitors in the adult hippocampal dentate gyrus give rise to newborn granule (GCs) cells that, when fully differentiated, receive synaptic inputs from entorhinal cortex and send axons along the mossy fiber pathway to form synaptic outputs with CA3 pyramidal neurons. We and others have shown that it takes about eight weeks for the newborn GCs to fully differentiate and form mature synaptic inputs and outputs. The major focus of this proposal is to determine the molecular changes in the synaptic outputs when newborn mossy fiber boutons from GC are forming synapses with mature CA3 pyramidal cells. We propose to use superresolution immunofluorescent array tomography and conjugate array tomography coupled with electron microscopy to profile the proteomic changes of the pre- and post-synaptic elements during the establishment of mature synapses. We have found that to establish a mature synaptic contact the mossy fiber can either 1) form a de novo nascent synapse or 2) replace an existing mossy fiber bouton assuming control of the existing postsynaptic CA3 dendrite. The molecular mechanisms regulating these disparate cellular processes are unknown. Here we will use array tomography analysis to profile the proteomic changes in these synapses to test the hypothesis that the synaptic molecular composition of integrating newborn neurons in adult hippocampus is highly dynamic during the entire maturation process. We have two main focuses: (1) to establish a proteomic profile of the developing and mature presynaptic mossy fiber terminal during adult hippocampal neurogenesis and (2) to establish a proteomic profile of the developing and mature postsynaptic mossy fiber terminal during adult hippocampal neurogenesis. These experiments will be the first to address the intricate proteomic changes essential for establishing new synaptic outputs during adult neurogenesis and will potentially identify a pharmacological target for therapeutic strategies to improve the function of adult brain.
Adult neurogenesis impacts cognitive function and therefore is an important molecular and cellular target for therapies aimed at improving cognition or treating cognitive disability. The studies described in this proposal will use a novel array tomography approach to reveal molecular proteomic changes that co-regulate with synaptic integration of newborn neurons in adult hippocampus. Understanding the mechanisms of how the newborn neurons integrate into mature neural circuits will help identify novel therapeutic targets for preventing and treating diseases related to cognitive decline in the brain.
