Gadd45b knockout mice exhibit selective deficits in hippocampus-dependent long-term memory

Abstract

Growth arrest and DNA damage-inducible b (Gadd45b) has been shown to be involved in DNA demethylation and may be important for cognitive processes. Gadd45b is abnormally expressed in subjects with autism and psychosis, two disorders associated with cognitive deficits. Furthermore, several high-throughput screens have identified Gadd45b as a candidate plasticity-related gene. However, a direct demonstration of a link between Gadd45b and memory has not been established. The current studies first determined whether expression of the Gadd45 family of genes was affected by contextual fear conditioning. Gadd45b, and to a lesser extent Gadd45g, were up-regulated in the hippocampus following contextual fear conditioning, whereas Gadd45a was not. Next, Gadd45b knockout mice were tested for contextual and cued fear conditioning. Gadd45b knockout mice exhibited a significant deficit in long-term contextual fear conditioning; however, they displayed normal levels of short-term contextual fear conditioning. No differences between Gadd45b knockout and wild-type mice were observed in cued fear conditioning. Because cued fear conditioning is hippocampus independent, while contextual fear conditioning is hippocampus dependent, the current studies suggest that Gadd45b may be important for long-term hippocampus-dependent memory storage. Therefore, Gadd45b may be a novel therapeutic target for the cognitive deficits associated with many neurodevelopmental, neurological, and psychiatric disorders.

Object-location training elicits an overlapping but temporally distinct transcriptional profile from contextual fear conditioning

“…The genes were chosen for well-studied expression changes ( Arc, Bdnf4, Egr1, Fos, Homer1 ), genes our lab has previously studied [ Fosl2 (Hawk et al, 2012), Gadd45 family (Leach et al, 2012)], or from microarray data (Btg2, Cpeb3, Histh2hab, Sik1, Sox18, Tob1, Tob2 (Peixoto et al, 2013)). cDNA samples underwent specific target amplification and were run on a 96.96 Fluidigm Biomark HD plate in triplicate (96 genes, 32 samples).…”

Epigenetic regulation of estrogen-dependent memory

“…However, the role of Gadd45b in hippocampal memory is unclear. Although contextual fear conditioning rapidly increases hippocampal Gadd45b mRNA levels in mice (Leach et al, 2012; Sultan et al, 2012), Gadd45b knockout has been reported to both impair (Leach et al, 2012) and enhance (Sultan et al, 2012) hippocampal-dependent memory. Nevertheless, these data support some involvement of DNA demethylation in hippocampal plasticity and memory (Sultan and Sweatt, 2013).…”

Molecular Genetic Strategies in the Study of Corticohippocampal Circuits

“…Knockout technologies have also been used to show the importance of posttranslational DNA modifications for learning and memory. For example, knocking out Gadd45b, a gene involved in activity-induced DNA methylation, results in abnormal dendritic development of newborn neurons in the adult brain, deficient long-term contextual fear memory, and the reduction of genes necessary for adult neurogenesis Leach et al 2012). Moreover, knockout of the cyclic adenosine monophosphate (cAMP) response element-binding (CREB) protein (CBP), which can act as a histone acetyltransferase, impairs long-term fear and object-recognition memory and well as LTP (Alarcó n et al 2004).…”