Effects of elevated glucocorticoids on hippocampal morphology and function

Glucocorticoids (GCs) are secreted by the adrenal glands as an endocrine response to stress, and are endogenously elevated in numerous neuropsychological disorders (e.g., depression, Cushing's syndrome, anorexia nervosa). Corticosterone (CORT), the predominant glucocorticoid in rodents, causes dendritic changes in neurons of the CA3 subfield of the hippocampus, a structure involved in learning and memory. Although dendritic changes may imply synapse loss, they are not a direct measure of synapse number. The present studies were designed to directly test the hypothesis that chronically elevated CORT decreases synapse numbers in the hippocampus. Effects on memory, behavioral activity and exploration were also examined.; In Experiment 1 we tested whether 2-month CORT administration (40mg/kg) affects hippocampal cellular and ultrastructural integrity and behavior in adult male rats. Application of unbiased stereological techniques and quantitative anatomical methods in tissue prepared for either light or electron microscopic analysis showed that CORT administration decreased the volume of the middle CA3 apical dendritic neuropil and reduced the total number of synapses in CA3. CORT did not reduce neuron number, suggesting that synapse loss was not the result of neuron loss, but instead adaptation of neurons. In addition, CORT reduced the mitochondrial, but not glial volume in the middle CA3. The anatomical changes were accompanied by suppression of behavioral activity.; In experiment 2 we investigated CORT effects on exploratory forms of behavior. Male adult rats were injected with CORT (27mg/kg) or vehicle (sesame oil) for 21 days and then tested in an open field. Behavioral analysis indicated that glucocorticoid elevations reduced exploration. Non-ambulatory movements were not affected.; The results confirm the popular, but untested, hypothesis that chronic elevations of glucocorticoids reduce synapse numbers in the entire CA3 apical dendritic neuropil. A corresponding reduction in mitochondrial volume presumably resulted from the reduced energy demands associated with synapse loss. The volume and synapse loss were associated with memory deficits and reduced behavioral activity. In addition, elevated GCs impair exploratory behavior. Our findings suggest that chronically elevated GCs may reduce hippocampal volume in some human disorders, and may be responsible for some behavioral alterations associated with these disorders.