Control of the establishment of aversive memory by calcineurin and Zif268

Abstract

Emotional memory is a rapidly acquired and persistent form of memory, and its robustness is in part determined by the initial strength of the memory. Here, we provide new evidence that the protein phosphatase calcineurin (CaN), a potent negative regulator of neuronal signaling that is known to constrain learning and memory, critically regulates the establishment of emotional memory through mechanisms involving the immediate early gene Zif268 (also known as Egr1). We found that CaN is inhibited in the amygdala during the establishment of aversive memory, but Zif268 is activated. Using inducible transgenesis in mice, we further saw that CaN inhibition and Zif268 overexpression during memory establishment strengthen the memory trace and enhance its resistance to extinction. We found that CaN inhibition correlates with increased Zif268 expression and that a common pool of proteins is regulated in the amygdala after CaN inhibition and Zif268 overexpression. Together, these findings reveal a previously unknown mechanism for the control of emotional memory that depends on CaN and Zif268.

Zif268 / Egr1 gain of function facilitates hippocampal synaptic plasticity and long-term spatial recognition memory

“…Whereas targeted deletion of the Zif268 gene results in profound impairments of several forms of long-term memory, including a fundamental memory ability, recognition memory [1,2,15,27], here we report that overexpression of Zif268 in forebrain neurons in mice is sufficient to augment the mice's ability to form a long-lasting spatial recognition memory. These findings, together with the demonstration that Zif268 overexpression can slow down extinction of conditioned taste aversion [8], clearly add to the growing evidence that Zif268 brain expression is an important factor for establishing stable long-lasting memories.…”

“…Zif268 mRNA and protein are also rapidly induced in association with LTP and in defined brain structures following learning or recall of several types of memory (see [5,6] for reviews) and this can lead to a functional increase in Zif268 protein binding to its DNA consensus Egr response element (ERE) [7]. Using a gain-of-function strategy in transgenic mice, a recent study reported that enhanced neuronal expression of Zif268 can slow down extinction of conditioned taste aversion [8]. As resistance to extinction can be taken as a sign of stronger memory formed during initial training, this raises the question of whether Zif268 overexpression can directly facilitate the formation of long-term memory.…”

Calcineurin inhibition blocks within-, but not between-session fear extinction in mice

“…Animals with a forebrain-specific CaN knockout have normal reference memory in the water maze, but show impaired performance in the delayed-match-to-place version of the task (Zeng et al 2001), indicating that CaN might be important for the modification of previously learned behavioral responses. Mice with genetic inhibition of calcineurin activity also present enhanced initial learning of some tasks (Malleret et al 2001;Baumgärtel et al 2008;Havekes et al 2008;de la Fuente et al 2014) but impaired extinction of taste and contextual fear conditioning (Baumgärtel et al 2008;Havekes et al 2008). Moreover, CaN activity in the amygdala seems to be unaltered (Lin et al 2003a) or repressed during initial learning (Baumgärtel et al 2008), but both its activity (Lin et al 2003a) and protein content (Merlo et al 2014) in the amygdala and its nuclear content in the hippocampus (de la Fuente et al 2011) are increased after extinction.…”

“…Mice with genetic inhibition of calcineurin activity also present enhanced initial learning of some tasks (Malleret et al 2001;Baumgärtel et al 2008;Havekes et al 2008;de la Fuente et al 2014) but impaired extinction of taste and contextual fear conditioning (Baumgärtel et al 2008;Havekes et al 2008). Moreover, CaN activity in the amygdala seems to be unaltered (Lin et al 2003a) or repressed during initial learning (Baumgärtel et al 2008), but both its activity (Lin et al 2003a) and protein content (Merlo et al 2014) in the amygdala and its nuclear content in the hippocampus (de la Fuente et al 2011) are increased after extinction. Finally, blockade of calcineurin activity in the hippocampus (de la Fuente et al 2011) or of its expression in the amygdala (Merlo et al 2014) can disrupt extinction of fear conditioning, and its inhibition in the amygdala interferes with memory destabilization during reconsolidation of an inhibitory avoidance memory (Fukushima et al 2014).…”

The exclusive induction of extinction is gated by BDNF

“…It appears that Zif268 inhibition facilitates extinction, and that Zif268-mediated events in the hippocampus may therefore protect against or act to prevent extinction at least in the short-term. However, a more recent study in which Zif268 was conditionally overexpressed in the forebrain failed to show changes in the extinction of conditioned taste aversion (CTA) (Baumgartel et al 2008). However, the failure to observe a role for Zif268 in extinction may be due to the already high levels of Zif268 in the insular cortex, a structure integral for CTA, occluding the effect of additional protein on the behavior.…”