Effect of Hippocampal CREB Deletion on Models of Anxiety, Depression, and Antidepressant Response

Depression is the most common psychiatric disorder, yet current antidepressants are inadequate as they require weeks of treatment to alleviate symptoms. The mechanism by which the immediate effects of antidepressants cause later behavioral improvements remains unknown, focusing research on downstream signaling events triggered by antidepressant administration. Expression and activity of the transcription factor CREB are increased by antidepressant drugs, and CREB targets include genes known to be involved in antidepressant response. However, the effects of manipulating CREB depend on the brain region examined, with initial studies showing an antidepressant role for CREB in the hippocampus. To investigate the hippocampal-specific importance of CREB in depression-related behaviors and response to antidepressant drugs, we used CrebloxP/loxP mice, in which CREB deletion could be induced by injection of an adeno-associated virus expressing Cre recombinase. Robust and specific deletion of CREB protein throughout the hippocampus was achieved via viral injection to this region in adult mice. Acute response to antidepressants in the forced swim test, a common behavioral assay for antidepressant efficacy, was unaffected by hippocampal CREB deletion. In an assay sensitive to chronic antidepressant response, the novelty-induced hypophagia (NIH) paradigm, hippocampal CREB deletion did not alter response to chronic antidepressant treatment. However, mice with hippocampal deletion of CREB also responded to acute antidepressant treatment in the NIH, an accelerated response to antidepressants, as control mice responded only to chronic, but not acute, treatment in this paradigm. Additionally, loss of CREB from the hippocampus increased hippocampal neurogenesis, which may be related to the accelerated response to antidepressants in the NIH in these mice. These results mimic the phenotype of a constitutive knockout of CREB, suggesting that the phenotype does not result from developmental loss of CREB. The CREB-family protein CREM was upregulated following deletion of CREB, demonstrating that regulation within this family is highly dynamic. CREM may functionally compensate for the lack of CREB by maintaining or increasing expression of CREB target genes, including Bdnf and Bcl-2. These genes are known to regulate cell survival and differentiation, and may contribute to the observed increase in hippocampal neurogenesis, although further study is necessary to confirm this hypothesis. This work indicates that CREB family proteins are important regulators of hippocampal neurogenesis and behaviors associated with antidepressant response. However, behavioral results suggest that CREB in the hippocampus may not be necessary for the behavioral response to antidepressants, challenging a previous study that suggested increased CREB activity was sufficient to produce an antidepressant behavioral response. This mouse model of specific loss of CREB function will be useful in dissecting the role of CREB in specific brain regions, potentially resolving this discrepancy. Overall, future study of the role of CREB and its targets in the downstream mechanisms of antidepressant response may contribute to the development of novel therapeutics