cAMP Response Element-Binding Protein Deficiency Allows for Increased Neurogenesis and a Rapid Onset of Antidepressant Response

Abstract

cAMP response element-binding protein (CREB) has been implicated in the molecular and cellular mechanisms of chronic antidepressant (AD) treatment, although its role in the behavioral response is unclear. CREB-deficient (CREB ␣⌬ mutant) mice demonstrate an antidepressant phenotype in the tail suspension test (TST) and forced-swim test. Here, we show that, at baseline, CREB ␣⌬ mutant mice exhibited increased hippocampal cell proliferation and neurogenesis compared with wild-type (WT) controls, effects similar to those observed in WT mice after chronic desipramine (DMI) administration. Neurogenesis was not further augmented by chronic DMI treatment in CREB ␣⌬ mutant mice. Serotonin depletion decreased neurogenesis in CREB ␣⌬ mutant mice to WT levels, which correlated with a reversal of the antidepressant phenotype in the TST. This effect was specific for the reversal of the antidepressant phenotype in these mice, because serotonin depletion did not alter a baseline anxiety-like behavior in CREB ␣⌬ mutant mice. The response to chronic AD treatment in the novelty-induced hypophagia (NIH) test may rely on neurogenesis. Therefore, we used this paradigm to evaluate chronic AD treatment in CREB ␣⌬ mutant mice to determine whether the increased neurogenesis in these mice alters their response in the NIH paradigm. Whereas both WT and CREB ␣⌬ mutant mice responded to chronic AD treatment in the NIH paradigm, only CREB ␣⌬ mutant mice responded to acute AD treatment. However, in the elevated zero maze, DMI did not reverse anxiety behavior in mutant mice. Together, these data show that increased hippocampal neurogenesis allows for an antidepressant phenotype as well as a rapid onset of behavioral responses to AD treatment.

Abstinence following Alcohol Drinking Produces Depression-Like Behavior and Reduced Hippocampal Neurogenesis in Mice

“…Finally, our results showing that desipramine did not alter FST performance in or neurogenesis in control mice are somewhat surprising. Another study demonstrated that chronic desipramine treatment increases neurogenesis and decreases depression-like behavior in control mice; however, that study used utilized twice-daily administration of 12.5 mg/kg desipramine (Gur et al, 2007), indicating that a higher dose may have produced changes in our control animals. Additionally, although acute desipramine treatment has been shown to reduce immobility in the FST (Lucki et al, 2001), we did not administer desipramine on the day of the test.…”

The Neuropeptide VGF Is Reduced in Human Bipolar Postmortem Brain and Contributes to Some of the Behavioral and Molecular Effects of Lithium

“…The cage was also sprayed with a cleaner (Pine Sol), and the experiment was performed in a novel testing room with no acclimation period. A failure to consume any milk was recorded as 15 min latency (Gur et al, 2007).…”

“…(Gur et al, 2007) for 21 d to VGF ϩ/Ϫ and WT mice that had been trained to drink the sweetened condensed milk. Our results confirm that DMI injections administered intraperitoneally reduce the latency to drink in the novel environment relative to saline controls (F (2,13) ϭ 3.765, Fisher's p ϭ 0.0169) but had no effect on latency in the home cage on either day of testing (F (2,13) ϭ 0.875, Fisher's p ϭ 0.2566; F (2,13) ϭ 0.415, Fisher's p ϭ 0.8236).…”

Lipid Rafts, G Proteins and the Etiology of and Treatment for Depression: Progress toward a Depression Biomarker

“…Closely related to this is the regulation of cAMP response element binding protein (CREB) levels in depression and by antidepressant treatment. A comprehensive review by Blendy indicates that there is evidence for both increased and decreased levels of CREB and pCREB following chronic treatment with certain antidepressants [2], and a later study discovered that CREB-deficient mice display a 'depression-resistant' phenotype [3].…”

“…Thus, it appears that antidepressants may exert their observed effects on cAMP signaling by liberating G sα from TX-100-resistant membrane domains, where it accumulates during the course of depression. Furthermore, the ratio of TX-100-soluble to TX-100-resistant G sα may prove to be a useful biomarker for human depression and a rapid (3)(4) No writing assistance was utilized in the production of this manuscript.…”