Synapse loss from chronically elevated glucocorticoids: Relationship to neuropil volume and cell number in hippocampal area CA3

Abstract

Individuals with clinical disorders associated with elevated plasma glucocorticoids, such as major depressive disorder and Cushing's syndrome, are reported to have smaller hippocampal volume. To understand how the hippocampus responds at the cellular and subcellular levels to glucocorticoids and how such changes are related to volume measures, we have undertaken a comprehensive study of glucocorticoid effects on hippocampal CA3 volume and identified elements in the neuropil including astrocytic volume and cell and synapse number and size. Male Sprague-Dawley rats were injected with corticosterone (40 mg/kg), the primary glucocorticoid in rodents, or vehicle for 60 days. The CA3 was further subdivided so that the two-thirds of CA3 (nearest the dentate gyrus) previously shown to be vulnerable to corticosterone could be analyzed as two separate subfields. Corticosterone had no effect on neuropil volume or glial volume in the proximal subfield but caused a strong tendency for astrocytic processes to make up a larger proportion of the tissue and for volume of tissue made of constituents other than glial cells (primarily neuronal processes) to be smaller in the middle subfield. Within the neuropil, there were no cellular or subcellular profiles that indicated degeneration, suggesting that corticosterone does not cause prolonged damage. Corticosterone did not reduce cell number or cell or nonperforated synapse size but did cause a pronounced loss of synapses. This loss occurred in both subfields and, therefore, was independent of volume loss. Together, the findings suggest that volume measures can underestimate corticosterone effects on neural structure.

Hippocampal volume and declarative memory function in combat-related PTSD

“…If the impact of dentate atrophy on the volume of the hippocampus was proportional, and the dentate contributed 20% of the hippocampal cross-section, a halving of the dentate would be required to produce only a 20% decrease in the parent structure. It is also germane here that glucocorticoid-driven depletion of mitochondria (Coburn-Litvak et al, 2004 ) and synaptic numbers (Tata, Marciano, & Anderson, 2006 ) have been observed in rat hippocampus in the absence of smaller volume.…”

Brain-Derived Neurotrophic Factor Signaling Rewrites the Glucocorticoid Transcriptome via Glucocorticoid Receptor Phosphorylation

“…Recent evidence suggests that BDNF and glucocorticoid have converging, homeostatic effects in the nervous system (recently reviewed in references 27, 28, 29, and 30). For example, chronic stress or exogenous glucocorticoid administration suppresses hippocampal BDNF expression, resulting in neuronal atrophy and cognitive impairment (31)(32)(33).…”

Structural brain plasticity in adult learning and development

“…Though learning may be primarily related to synaptogenesis and dendritic branching, physical exercise may affect capillaries without increasing neural tissue (Black et al, 1990). In addition, glia may increase in a compensatory manner to balance decreases in synapses (Tata et al, 2006). Thus, experience-dependent volumetric changes cannot always be assumed to originate from changes in the number of synapses per neuron.…”