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The neural cell adhesion molecule, NCAM, is ubiquitously expressed within the CNS and has roles in development, cognition, neural plasticity and regulation of the immune system. NCAM is thus potentially an important pharmacological target for treatment of brain diseases. A cell adhesion mimetic FGL, a 15 amino-acid peptide derived from the second fibronectin type-III module of NCAM, has been shown to act as a neuroprotective agent in experimental disease and ageing models, restoring hippocampal/cognitive function and markedly alleviating deleterious changes in the CNS. However, the effects of FGL on the hippocampus of young healthy rats are unknown. The present study has examined the cellular neurobiological consequences of subcutaneous injections of FGL, on hippocampal cell morphometry in young (4 month-old) rats. We determined the effects of FGL on hippocampal volume, pyramidal neuron number/density (using unbiased quantitative stereology), and examined aspects of neurogenesis (using 2D morphometric analyses). FGL treatment reduced total volume of the dorsal hippocampus (associated with a decrease in total pyramidal neuron numbers in CA1 and CA3), and elevated the number of doublecortin immunolabeled neurons in the dentate gyrus, indicating a likely influence on neurogenesis in young healthy rats. These data indicate that FGL has a specific age dependent effect on the hippocampus, differing according to the development and maturity of the CNS.

Advanced ageing is associated with hippocampal deterioration and mild cognitive decline. The hippocampal subregion CA3 stratum lucidum (CA3-SL) receives neuronal inputs from the giant mossy fibre boutons of the dentate gyrus, but relatively little is known about the integrity of this synaptic connection with ageing. Using serial electron microscopy and unbiased stereology, we examined age-related changes in mossy fibre synapses on CA3 thorny excrescences within the CA3-SL of young adults (4-month-old), middle-aged (12-month-old), and old-aged (28-month-old) Wistar rats. Our data show that while there is an increase in CA3 volume with ageing, there is a significant (40–45%) reduction in synaptic density within the CA3-SL of 12- and 28-month-old animals compared with 4-month-old animals. We also present preliminary data showing that the CA3 neuropil in advanced ageing was conspicuously full of lipofuscin and phagolysosome positive, activated microglial cellular processes, and altered perivascular pathology. These data suggest that synaptic density in the CA3-SL is significantly impaired in ageing, accompanied by underlying prominent ultrastructural glial and microvascular changes.