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

Abstract

Growth arrest and DNA damage-inducible β (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.

Figure 1.

Comparison of hippocampal Gadd45 family gene expression after contextual fear conditioning in C57BL/6J mice. (A) Gadd45b and Gadd45g mRNA were up-regulated in the hippocampus after contextual fear conditioning (1.5-mA footshock) compared with homecage (handled-only) controls. (B) Gadd45b mRNA was up-regulated in the hippocampus after contextual fear conditioning (2 × 0.57-mA footshocks) and context-only exposure compared with homecage (handled-only) controls. Error bars, ±SEM. (*) Significantly different from the homecage (handled-only) group (P < 0.05).

Figure 2.

Comparison of long-term (24-h) contextual fear conditioning in Gadd45b WT and KO mice. Gadd45b KO mice froze significantly less to the context than WT mice. Error bars, ±SEM. (*) Significantly different from WT (P < 0.05).

Figure 3.

Comparison of short-term (1-h) contextual fear conditioning in Gadd45b WT and KO mice. Gadd45b KO mice froze to the same extent to the context as WT mice. Error bars, ±SEM.

Figure 4.

Comparison of hippocampal Gadd45 family gene expression after contextual fear conditioning in Gadd45b KO and WT mice. Gadd45a and Gadd45g were unchanged in KO animals compared with WT controls, while Gadd45b expression was completely eliminated. Error bars, ±SEM.

Figure 5.

Comparison of long-term (24-h) cued fear conditioning in Gadd45b WT and KO mice. Gadd45b KO mice froze to the same extent to the cue as WT mice. Error bars, ±SEM.