P033 - AGE-RELATED NEUROINFLAMMATION AND PATHOLOGY IN THE LOCUS COERULEUS AND HIPPOCAMPUS: BETA-ADRENERGIC ANTAGONISTS EXACERBATE IMPAIRMENT OF LEARNING AND MEMORY IN AGED MICE (ID 1741)
Abstract
Aims
The locus coeruleus (LC) is the main source of noradrenergic input to the forebrain and hippocampus, and may be vulnerable to degeneration and contribute to age-related cognitive decline and neuroinflammation. This study was designed to test the effects of age and the acute effects of beta-adrenergic agonist and antagonist on pathology in the LC and hippocampus.
Methods
Behavioral Testing, Immunohistochemistry, Western Blot, Multiplex mouse cytokine assay, Proteomics
Results
An increase in hippocampal and LC microgliosis and inflammatory proteins in the hippocampus was detected in aged mice. We report pathological hyperphosphorylation of the postsynaptic NMDA receptor subunit 2B (NR2B) in the hippocampus, suggesting neuronal hyperexcitability. Furthermore, the aged proteome revealed an induction in proteins related to energy metabolism, and mitochondria dysfunction in the LC and hippocampus. In a series of hippocampal dependent behavioral assessment tasks, acute beta-adrenergic agonist or beta blocker administration altered learning and memory behavior in both aged and young mice.
Conclusions
In summary, our data provide evidence for age-related neuroinflammation in the locus coeruleus and hippocampus alongside evidence for metabolic challenge in the locus coeruleus and extrasynaptic deficiency of NMDA receptor signaling in the hippocampus. This cognitive impairment in aged mice is exacerbated with acute beta-blocker delivery. Further studies are needed to understand mechanisms linking metabolic stress, neuroinflammatory signaling from astrocytes and microglia, and the extra-synaptic pathology. Future studies will be needed to explore the impact of long-term exposure to beta-blockers on neuroinflammation, brain pathology, and behavioral function.
