Friday, April 26, 2024
4/26/2024
Project Summary Noradrenergic (NA) input to hippocampus from locus coeruleus (LC), the sole supplier of NA innervation to forebrain, is required for acquisition and consolidation of spatial learning and memory and contextual fear behavior. The dentate gyrus (DG) contains the highest NA content, greatest NA fiber density, and largest expression of ß1-and ß2-adrenergic receptors (ARs) in the hippocampal formation, consistent with DG being a key region of modulatory control by LC. There is a rich literature dating back to the mid 1980’s showing a critical role for ß-ARs in facilitating induction of both LTP and LTD at DG synapses depending upon the saliency of the experience. This heightened plasticity occurs simultaneous with heightened learning and memory, and both are prevented by loss of NA innervation or pharmacological blockade of ß-ARs. Importantly, the LC in females has a larger volume, LC neurons have greater dendritic arbors, and at proestrus, when plasma estradiol levels are the highest, NA neuronal activity is decreased. The LC is the first brain region damaged in Alzheimer’s disease (AD), due to accumulation of hyper- phosphorylated tau (p-tau). The consequence of this pathology is greatly under-appreciated since transgenic AD mouse models do not recapitulate this feature of human disease. Fortunately, the novel TgF344-AD rat model has significant p-tau accumulation in LC and NA axon loss in hippocampus, permitting detailed studies of LC and NA system dysfunction on hippocampal synaptic transmission and learning and memory. Clearly, identifying strategies to prevent p-tau accumulation and LC damage is critical. The post-translational modification, O- GlcNAcylation, has been shown to do just this through competition with phosphorylation at key serine residues on p-tau that cause its accumulation. Using brain slice electrophysiology, we reported pathologically heightened LTP at medial perforant path synapses in dentate gyrus prior to CA1 synapses in both sexes. In recent data, we find heightened potentiation at medial perforant path synapses following pharmacological activation of ß-ARs. This upregulation of ß-AR function in the context NA fiber loss likely drives the heightened LTP and masks deficits in learning and memory early in the disease. The current proposal will test the hypothesis that hippocampal noradrenergic function in AD is impaired via aberrant excitability of LC-NA cells caused by progressive p-tau accumulation and through NA denervation, both of which will be worse in ovariectomized females and protected by O-GlcNAcylation. We will use a combination of electrophysiology in hippocampus and locus coeruleus, hippocampus-dependent behavior, pharmacology, biochemistry, and O-GlcNAc biology to test this innovative hypothesis. Outcomes will shed new light on the role of LC damage in AD, and will lay the ground work for therapeutic strategies targeting the LC and perhaps O-GlcNAcylation.
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