Restructuring the neuronal stress response with anti-glucocorticoid gene delivery

Abstract

Glucocorticoids, the adrenal steroids released during stress, compromise the ability of neurons to survive neurological injury. In contrast, estrogen protects neurons against such injuries. We designed three genetic interventions to manipulate the actions of glucocorticoids, which reduced their deleterious effects in both in vitro and in vivo rat models. The most effective of these interventions created a chimeric receptor combining the ligand-binding domain of the glucocorticoid receptor and the DNA-binding domain of the estrogen receptor. Expression of this chimeric receptor reduced hippocampal lesion size after neurological damage by 63% and reversed the outcome of the stress response by rendering glucocorticoids protective rather than destructive. Our findings elucidate three principal steps in the neuronal stress-response pathway, all of which are amenable to therapeutic intervention.

Enhancing Cognition after Stress with Gene Therapy

“…A previous study examined the beneficial effects of ER/GR in the realm of an excitotoxic insult (Kaufer et al, 2004). We now investigate whether ER/GR would also be beneficial in the cognitive realm.…”

“…In the present report, we use gene therapy with a chimeric gene ("ER/GR") containing the hormone-binding domain of the GC receptor and the DNA binding domain of the estrogen receptor; this construct converts the actions of GCs at the receptor level into estrogenic effects at the transcriptional level, thereby converting deleterious GC effects into beneficial estrogenic ones (Kaufer et al, 2004).…”

Viral vector-mediated blockade of the endocrine stress–response modulates non-spatial memory

“…ER/GR is a modular chimeric gene that consists of the C-terminal hormone-binding domain of the glucocorticoid receptor and the N-terminal DNA-binding domain of the primary human estrogen receptor ERα [6,2]. ER/GR, when expressed, has the dual effects of competing with endogenous GR for GCs and converting GR-mediated signaling into neurotrophic ER responses [6]. In this study, we assessed if expression of ER/GR in the dentate gyrus could block the disruptive effects of stress on non-spatial memory.…”

“…In this study, we assessed if expression of ER/GR in the dentate gyrus could block the disruptive effects of stress on non-spatial memory. The construction of the ER/GR amplicon vector has been previously described [6]. Briefly, for stereotaxic infusion of vector, rats were anesthetized with 1ml/kg of a mixture consisting of 100 mg/kg ketamine, 10 mg/kg acepromazine, and 100 mg/kg xylazine.…”

“…Stereotaxic infusion of HSV vectors preferentially infects neurons over glia (85% of neurons, 10-15% glia) up to several millimeters from the infusion site [6,9]. Although infection is confined to a small region, studies show that altering function in this small area is sufficient to influence hippocampus-dependent behavior [46,47].…”