The hippocampus undergoes several structural, cellular, and functional changes during normal aging which is directly associated with cognitive decline and the pathogenesis of neurodegenerative disease. Dysregulation of innate immune function in the peripheral and central nervous system during aging is thought to contribute to reduced cognition and the pathophysiological events leading to neurodegeneration. Most studies of aging compare young individuals with elderly, however there is limited investigation into whether hippocampal function also declines in early aging.
In this thesis I used in vitro electrophysiology on mouse hippocampal slices to examine hippocampal excitability along the perforant path in an early aging model, comparing neuronal activity between juvenile (9-15 weeks old) and adult (25-35 weeks old) C57BL/6J mice. I also examined if the Duffy antigen receptor for chemokines (DARC), which mediates circulating pro-inflammatory chemokine concentration, was affecting hippocampal excitability using homozygous DARC knockout mice.
Extracellular measurements of dentate gyrus neurons during perforant pathway stimulation showed that hippocampal excitability increases in early aging. Intracellular measurements of intrinsic membrane properties indicated that dentate gyrus granule neurons become hyperpolarised and have increased membrane resistance during early aging, which occurred only in the supra-pyramidal subregion. Bath application of chemokine CCL2 increased hippocampal excitability via its cognate receptor CCR2, however not in an age-dependent manner, indicating that CCL2 does not regulate early age-dependent excitability. Measurements of population excitability and granule cell intrinsic properties in DARC knockout mice indicated that DARC regulates neuronal excitability in early aging and resting membrane potential of supra-pyramidal granule neurons. Adult DARC knockout mice also had increased hippocampal microglia proliferation. These are the first reported effects of DARC deficiency on brain cells.
These implications of these findings, for our overall understanding of how hippocampal function changes in early aging and how chemokines and chemokine receptors alter hippocampal excitability, are discussed.
