Original articleExpression of the cAMP response element binding protein (CREB) in hippocampus produces an antidepressant effect
Introduction
Basic and clinical studies have provided evidence that the serotonin (5-HT) and norepinephrine (NE) neurotransmitter systems are involved in the treatment, and possibly the pathophysiology, of depression. These studies have led to a series of hypotheses concerning the mechanism of the action of antidepressants that have focused on alterations in levels of these monoamines and their receptors Duman et al 1997, Heninger and Charney 1987, Nestler 1998, Roth 1994. More recent studies have extended this work to an examination of the postreceptor intracellular targets that mediate the action of antidepressants. One such pathway is the cAMP signal transduction cascade Duman et al 1997, McEwen 1999. We have reported that the cyclic amp (cAMP) response element binding protein (CREB), a transcription factor that mediates many of the actions of the cAMP cascade on gene expression, is up-regulated by antidepressant treatment (see Duman et al 1997, McEwen 1999). CREB expression and function in hippocampus are increased by chronic administration of different classes of antidepressants, including selective 5-HT and NE reuptake inhibitors Nibuya et al 1996, Thome et al 2000. These findings raise the possibility that CREB is a common downstream target of antidepressant treatment.
CREB can also be activated by Ca2+-dependent protein kinases and could thereby serve as a target for 5-HT and NE receptors coupled to other second messenger pathways (Shaywitz and Greenberg 1999). Moreover, CREB is known to play an important role in neuronal plasticity and cell survival, and regulation of this transcription factor and its target genes could contribute to the cellular adaptations underlying the actions of antidepressant treatment Duman et al 2000, Shaywitz and Greenberg 1999, Silva et al 1998. To examine this possibility, we have employed the herpes simplex virus (HSV)–mediated gene transfer system to study the influence of CREB over-expression on behavioral models of depression, the learned helplessness and forced swim tests. Our group has effectively used the viral expression system to study the role of CREB and other proteins in behavioral models, validating their usefulness for testing the actions of CREB in the current study Carlezon et al 1997, Dowlatshahi et al 1998.
The learned helplessness and the forced swim paradigms are well-established paradigms that are responsive to antidepressant treatment Porsolt et al 1977, Seligman 1975. In the learned helplessness paradigm, exposure to uncontrollable, aversive stimuli profoundly disrupts the ability to learn to escape shocks in a large number of species, including mice, rats, and humans (see Thiebot et al 1992, Weiss and Kilts 1995, Willner 1984). These performance deficits are not observed in animals that are subjected to an identical, but controllable, stress. The escape deficit in this model is reduced by subchronic (5–7 days), but not acute, antidepressant treatment. This includes different classes of antidepressants (i.e., tricyclics, 5-HT selective reuptake inhibitors, monoamine oxidase inhibitors, electroconvulsive seizures, and atypical antidepressants). Animals exposed to inescapable shock also exhibit a variety of behavioral and physiological changes that have been compared to depressive symptoms in humans, including decreased motor activity, loss of appetite and weight, reduced performance in self-stimulation paradigms, and immunosuppression (see Thiebot et al 1992, Weiss and Kilts 1995). In the forced swim test, total immobility time is reduced by the majority of antidepressants when administered acutely (1 day) or subchronically, and the potency of antidepressants in this test significantly correlates with their clinical potency (see Thiebot et al 1992, Willner 1984).
The hippocampus is one of several limbic brain structures where adaptations of the cAMP-CREB cascade could contribute to the actions of antidepressant treatment. Preclinical studies have demonstrated that stress can cause atrophy or loss of CA3 pyramidal neurons and decrease the neurogenesis of dentate gyrus granule cells in the hippocampus (see Duman et al 1999, McEwen 1999, Sapolsky 1996). Stress is also reported to decrease the expression of brain-derived neurotrophic factor in hippocampus (Smith et al 1995). Moreover, clinical brain imaging studies demonstrate that the volume of the hippocampus is reduced in patients with depression or posttraumatic stress disorder Sheline et al 1996, Bremner et al 1995, Bremner et al 2000. These studies suggest that alterations of hippocampus could also contribute to the pathophysiology of depression. In the study presented here, we demonstrate that over-expression of CREB in the dentate gyrus of hippocampus produces an antidepressant-like response in two behavioral models of depression.
Section snippets
Animal treatment paradigms and surgery
Male Sprague Dawley rats (240–260 gm; Charles River) were group housed and maintained on a 12-hour light/dark cycle with access to food and water ad libitum. Surgery, if applicable, was performed in a small animal stereotaxic apparatus (Kopf, Tijunga, CA) under anesthesia with pentobarbital sodium solution (50 mg/kg i.p. injection, Abbott Laboratories, North Chicago, IL). Rats received bilateral dentate gyrus (relative to bregma: anterior/posterior = −3.8 mm; lateral = ±2.0 mm; dorsal/ventral =
Viral-mediated over-expression of CREB
Microinjections of HSV-CREB or HSV-LacZ intended for dentate gyrus were aimed at the upper limb of the granular cell layer. Three days later the animals were perfused, and histological examination of the sections and expression of CREB and LacZ were determined. In rats injected with HSV-LacZ the expression of β-galactosidase was visualized via X-gal histochemistry and was abundantly expressed in the area around the injection site (Figure 1, upper right panel). This included the cell processes,
Discussion
The results of this study demonstrate that over-expression of CREB in the dentate gyrus of hippocampus improves performance in two behavioral models of depression, the learned helplessness and forced swim tests. These effects are specific to viral-mediated expression of CREB, because microinjection of HSV-LacZ did not significantly influence the behavioral responses in either paradigm. These behavioral models have been used extensively for pharmacological screening of antidepressant agents.
Acknowledgements
This work was supported by USPHS Grants MH45481 and 2 PO1 MH25642, and by a Veterans Administration National Center Grant for PTSD, VA Medical Center.
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