Inducible forebrain-specific ablation of the transcription factor Creb during adulthood induces anxiety but no spatial/contextual learning deficits.

Miriam A Vogt,Peter Gass,Dragos Inta,Marco A Riva,Hasan Elkin,Natascha Pfeiffer,Alessia Luoni

doi:10.3389/fnbeh.2014.00407

Abstract

The cyclic AMP (cAMP)-response element binding protein (CREB) is an activity-dependent transcription factor playing a role in synaptic plasticity, learning and memory, and emotional behavior. However, the impact of Creb ablation on rodent behavior is vague as e.g., memory performance of different Creb mutant mice depends on the specific type of mutation per se but additionally on the background and learning protocol differences. Here we present the first targeted ablation of CREB induced during adulthood selectively in principal forebrain neurons in a pure background strain of C57BL/6 mice. All hippocampal principal neurons exhibited lack of CREB expression. Mutant mice showed a severe anxiety phenotype in the openfield and novel object exploration test as well as in the Dark-Light Box Test, but unaltered hippocampus-dependent long-term memory in the Morris water maze and in context dependent fear conditioning. On the molecular level, CREB ablation led to CREM up regulation in the hippocampus and frontal cortex which may at least in part compensate for the loss of CREB. BDNF, a postulated CREB target gene, was down regulated in the frontal lobe but not in the hippocampus; neurogenesis remained unaltered. Our data indicate that in the adult mouse forebrain the late onset of CREB ablation can, in case of memory functionality, be compensated for and is not essential for memory consolidation and retrieval during adulthood. In contrast, the presence of CREB protein during adulthood seems to be pivotal for the regulation of emotional behavior.

Highlights

Inhibition of transcription factors or protein synthesis is hypothesized to block consolidation of short-term memory into long-term memory and affect emotional and depression-related circuits
The development of temporal and spatially restricted mutants using the Cre/loxP system allowed generating mutant mice with CREB ablation in forebrain neurons only (Mantamadiotis et al, 2002), this line was developed on a Crem negative background to avoid compensatory effects of Crem regulation, it is known that Crem ablation leads to altered emotional behavior and hyperactivity (Maldonado et al, 1999)
Crebflox/floxCamKCreERT2 mice were treated with tamoxifen at the age of 9–12 weeks, which resulted in the ablation of CREB in excitatory forebrain neurons including all principal neurons of the hippocampus (Figures 1A,B)

Summary

Introduction

Inhibition of transcription factors or protein synthesis is hypothesized to block consolidation of short-term memory into long-term memory and affect emotional and depression-related circuits. Due to the complex structure of the Creb gene with multiple exons and introns, the encoded proteins vary with splicing variants and different properties (Blendy et al, 1996; Mayr and Montminy, 2001). This creates a wide range of possibilities of genetic approaches to modify expression, formation or function of Creb (for an overview see Kida and Serita, 2014). Behavioral phenotyping aiming on emotional regulation was mostly focusing on depression-related changes, Crebα∆ mice, which carry

Methods

Results

Conclusion