Anti-glucocorticoid Gene Therapy Reverses the Impairing Effects of Elevated Corticosterone

Summary

Full Title: Anti-glucocorticoid gene therapy reverses the impairing effects of elevated corticosterone on spatial memory, hippocampal neuronal excitability, and synaptic plasticity

Abstract:

Moderate release of the major stress hormones, glucocorticoids (GCs), improves hippocampal function and memory. In contrast, excessive or prolonged elevations produce impairments. Enzymatic degradation and reformation of GCs help to maintain optimal levels within target tissues, including the brain. We hypothesized that expressing a GC-degrading enzyme in hippocampal neurons would attenuate the negative impact of an excessive elevation in GC levels on synaptic physiology and spatial memory. We tested this by expressing 11-beta-hydroxysteroid dehydrogenase (type II) in dentate gyrus granule cells during a 3 d GC treatment followed by examination of synaptic responses in hippocampal slices or spatial performance in the Morris water maze. In adrenalectomized rats with basal GC replacement, additional GC treatments for 3 d reduced synaptic strength and promoted the expression of long-term depression at medial perforant path synapses, increased granule cell and CA1 pyramidal cell excitability, and impaired spatial reference memory (without influencing learning). Expression of 11-beta-hydroxysteroid dehydrogenase (type II), mostly in mature dentate gyrus granule cells, reversed the effects of high GC levels on granule cell and pyramidal cell excitability, perforant path synaptic plasticity, ...

Full Title: Anti-glucocorticoid gene therapy reverses the impairing effects of elevated corticosterone on spatial memory, hippocampal neuronal excitability, and synaptic plasticity

Abstract:

Moderate release of the major stress hormones, glucocorticoids (GCs), improves hippocampal function and memory. In contrast, excessive or prolonged elevations produce impairments. Enzymatic degradation and reformation of GCs help to maintain optimal levels within target tissues, including the brain. We hypothesized that expressing a GC-degrading enzyme in hippocampal neurons would attenuate the negative impact of an excessive elevation in GC levels on synaptic physiology and spatial memory. We tested this by expressing 11-beta-hydroxysteroid dehydrogenase (type II) in dentate gyrus granule cells during a 3 d GC treatment followed by examination of synaptic responses in hippocampal slices or spatial performance in the Morris water maze. In adrenalectomized rats with basal GC replacement, additional GC treatments for 3 d reduced synaptic strength and promoted the expression of long-term depression at medial perforant path synapses, increased granule cell and CA1 pyramidal cell excitability, and impaired spatial reference memory (without influencing learning). Expression of 11-beta-hydroxysteroid dehydrogenase (type II), mostly in mature dentate gyrus granule cells, reversed the effects of high GC levels on granule cell and pyramidal cell excitability, perforant path synaptic plasticity, and spatial memory. These data demonstrate the ability of neuroprotective gene expression limited to a specific cell population to both locally and trans-synaptically offset neurophysiological disruptions produced by prolonged increases in circulating stress hormones. This report supplies the first physiological explanation for previously demonstrated cognitive sparing by anti-stress gene therapy approaches and lends additional insight into the hippocampal processes that are important for memory.
http://www.ncbi.nlm.nih.gov/pubmed/20130180

Citation:

Dumas TC, Gillette T, Ferguson D, Hamilton K, Sapolsky RM. Anti-glucocorticoid gene therapy reverses the impairing effects of elevated corticosterone on spatial memory, hippocampal neuronal excitability, and synaptic plasticity. J Neurosci, 2010, 30(5):1712-20. doi: 10.1523/JNEUROSCI.4402-09.2010.

My Contributions:

I worked on this project during a rotation in the PBNJ Lab (Physiological and Behavioral Neuroscience in Juveniles) with Dr. Ted Dumas in 2009. I began working on the project after the behavioral (Morris Water Maze) experiments had been carried out, and more electrophysiological experiments were required. Thus, I trained and then carried out adrenalectomies and cannulations for vector delivery (separate surgeries). The adrenalectomies were required in order to control the amount of corticosterone in the rats’ systems. A pellet of corticosterone, made by myself in the lab, was placed subcutaneously immediately after adrenalectomy to produce a baseline level of the hormone.

I was minimally involved in the actual electrophysiological recording, however I was tasked with embedding, sectioning, and visualizing slices for detection of green fluorescent protein (GFP – the signaling molecule used to detect insertion and production of the therapeutic gene) in the granule cells of the dentate gyrus. My contributions continued in the statistical analysis phase of the research, on both the e-phys and behavioral data.

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