Trace eyeblink conditioning requires the hippocampus but not autophosphorylation of αCaMKII in mice

Abstract

Little is known about signaling mechanisms underlying temporal associative learning. Here, we show that mice with a targeted point mutation that prevents autophosphorylation of ␣CaMKII (␣CaMKII T286A ) learn trace eyeblink conditioning normally. This forms a sharp contrast to the severely impaired spatial learning in the water maze and contextual fear conditioning observed in ␣CaMKII T286A mutants. Importantly, hippocampal lesions impaired trace eyeblink conditioning in ␣CaMKII T286A mice, suggesting a potential role of hippocampal ␣CaMKII-independent mechanisms. These results indicate that hippocampal signaling mechanisms that underlie temporal associative learning as assessed by trace eyeblink conditioning may differ from those of spatial and contextual learning.

Autophosphorylation of αCaMKII is differentially involved in new learning and unlearning mechanisms of memory extinction

“…In the hidden platform version of the water maze, animals learn to locate a submerged platform in a pool filled with opaque water. This hippocampus-dependent spatial navigation performance is profoundly impaired in homozygous ␣CaMKII T286A mutant mice (Giese et al 1998;Need and Giese 2003;Ohno et al 2005). In contrast, ␣CaMKII T286A+/-mice were normal in spatial learning in the water maze, since both the heterozygotes (F (4,30) = 2.88, P < 0.05) and wild-type controls (F (4,70) = 10.62, P < 0.05) showed similar reductions in their latencies to find the escape platform during acquisition (three sessions of two trials per day for 5 d) ( Fig.…”

“…We investigated the role of ␣CaMKII, a key molecular determinant of memory formation (Irvine et al 2006), in extinction of contextual fear and spatial memories by testing how a heterozygous T286A point mutation at the autophosphorylation site of this kinase (␣CaMKII T286A+/-) affects the mechanisms that extinguish memories. Although mice that are homozygous for the ␣CaMKII T286A mutation and deficient in autophosphorylation exhibit impairments in contextual fear conditioning and spatial learning in the water maze (Giese et al 1998;Ohno et al 2002Ohno et al , 2005Ohno et al , 2006Need and Giese 2003;Irvine et al 2005), ␣CaMKII T286A+/-mice were normal in the formation of contextual and spatial memories tested 24 h after training. Remarkably, the ␣CaMKII T286A+/-mutation prevented extinction of contex- Figure 3.…”

“…The ␣CaMKII T286A+/-mutation blocks extinction of contextual fear memory Our previous study demonstrated that mice homozygous for an ␣CaMKII T286A point mutation show impairments in hippocampus-dependent contextual fear conditioning, in which mice learn to associate a distinct context (CS) with an aversive foot shock (US) (Ohno et al 2005). In contrast, heterozygous ␣CaMKII T286A+/-mice were normal in contextual learning, since they exhibited a robust contextual freezing response (the absence of all but respiratory movements) that was comparable to wildtype controls when tested 24 h after training with one CS-US pairing (F (1,58) = 0.24, P > 0.05) (Fig.…”

“…It should be noted that a homozygous ␣CaMKII T 2 8 6 A mutation abolishes NMDA-receptor-dependent LTP at hippocampal Schaffer collateral-CA1 synapses (Giese et al 1998;Ohno et al 2002;Cooke et al 2006) and impairs contextual conditioning after a single training trial (Irvine et al 2005;Ohno et al 2005), while LTP is only attenuated, and considerable levels of LTP remain in the heterozygotes (Ohno et al 2002). It is reasonable to suppose that partial reductions in LTP may impact new learning mechanisms of extinction but the residual level of LTP may be enough to sustain initial fear learning in ␣CaMKII T286A+/-mutants, since the inhibitory association is formed by re-exposure to the context CS alone during extinction and thus, is more vulnerable to disruptions as compared with the excitatory association with CS-US pairing during fear memory acquisition.…”

“…A broad range of genetic lesions of ␣CaMKII signaling has been demonstrated to block both learning and LTP (Elgersma et al 2004). In particular, autophosphorylation of ␣CaMKII at threonine-286 in response to Ca 2+ influx, which switches the kinase into a Ca 2+ /calmodulin-independent or autonomously active state, provides a crucial step (Miller and Kennedy 1986;Fukunaga et al 1995;Tan and Liang 1996;Ouyang et al 1997;Rodrigues et al 2004), since knock-in mice with a targeted point mutation (T286A) that prevents autophosphorylation at this site exhibit deficits in hippocampal LTP and memory formation (Giese et al 1998;Ohno et al 2002Ohno et al , 2005Ohno et al , 2006Need and Giese 2003;Irvine et al 2005;Cooke et al 2006). Although the mechanisms by which ␣CaMKII autophosphorylation contributes to learning have been well documented, its role in memory extinction remains to be determined.…”