Hippocampal calpain is required for the consolidation and reconsolidation but not extinction of contextual fear memory.

Memory consolidation, reconsolidation, and extinction have been shown to share similar molecular signatures, including new gene expression. Calpain is a Ca-dependent protease that exerts its effects through the proteolytic cleavage of target proteins. Neuron-specific conditional deletions of calpain 1 and 2 impair long-term potentiation in the hippocampus and spatial learning.

Upregulation of CREB-mediated transcription enhances both short- and long-term memory.

Unraveling the mechanisms by which the molecular manipulation of genes of interest enhances cognitive function is important to establish genetic therapies for cognitive disorders. Although CREB is thought to positively regulate formation of long-term memory (LTM), gain-of-function effects of CREB remain poorly understood, especially at the behavioral level. To address this, we generated four lines of transgenic mice expressing dominant active CREB mutants (CREB-Y134F or CREB-DIEDML) in the forebrain that exhibited moderate upregulation of CREB activity.

[Mechanisms of reconsolidation and extinction of fear memory].

Reconsolidation and extinction of fear memories are induced by re-exposure to the conditioned stimulus (CS) but they appear to be opposite processes; as the fear memory is maintained or inhibited through reconsolidation and extinction, respectively. More importantly, reconsolidation and extinction are thought to be potential targets for the treatment of Post Traumatic Stress Disorder (PTSD). From this view, it is important to understand mechanisms by which reactivated fear memories are reconsolidated or extinguished.

Brain region-specific gene expression activation required for reconsolidation and extinction of contextual fear memory.

During fear conditioning, animals learn an association between a previously neutral or conditioned stimulus (CS) and an aversive or unconditioned stimulus (US). Subsequent reexposure to the CS alone triggers two competing processes. Brief reexposure to the CS initiates reconsolidation processes that serve to stabilize or maintain the original CS-US memory.

PLCgamma2 Activates CREB-dependent Transcription in PC12 Cells Through Phosphorylation of CREB at Serine 133.

The cAMP and Ca(2+) signaling pathways activate the transcription factor CREB through its phosphorylation at Serine 133. Activation of CREB is involved in the regulation of various biological phenomena. To understand further the mechanisms of the regulation of CREB activity in response to activation of the cAMP and Ca(2+) signaling pathways, we examined the roles of PLCgammas in CREB activation in PC12 cells.

Upregulation of calcium/calmodulin-dependent protein kinase IV improves memory formation and rescues memory loss with aging.

Previous studies have suggested that calcium/calmodulin-dependent protein kinase IV (CaMKIV) functions as a positive regulator for memory formation and that age-related memory deficits are the result of dysfunctional signaling pathways mediated by cAMP response element-binding protein (CREB), the downstream transcription factor of CaMKIV. Little is known, however, about the effects of increased CaMKIV levels on the ability to form memory in adult and aged stages. We generated a transgenic mouse overexpressing CaMKIV in the forebrain and showed that the upregulation of CaMKIV led to an increase in learning-induced CREB activity, increased learning-related hippocampal potentiation, and enhanced consolidation of contextual fear and social memories.