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dependent synaptic plasticity was demonstrated using mice carrying a point mutation of α
CaMKII at Thr286 to Ala (T286A)
(Giese et al., 1998). In α CaMKII T286A mutant mice,
experience-dependent plasticity in the barrel cortex was prevented in adult and adolescent
mice homozygous for the mutation, but was normal in heterozygotes and wild-type
littermates (Glazewski et al., 2000). The spatial tuning of place fields of α CaMKII T268A
mutant mice is initially similar to that of wild-type mice, but completely failed to show an
experience-dependent increase over days (Cacucci et al., 2007). α CaMKII T268A mutant
mice also show impairments in ocular dominance plasticity (Taha et al, 2002).
Several lines of transgenic mice have been generated to increase CaMKII activity levels,
such as transgenic T286D mutants with autonomous CaMKII activity. The mutant mice
expressing α CaMKII T268D exhibited normal LTP in response to stimulation at 100 Hz.
However, at lower frequencies, in the range of 1-10 Hz, there was a systematic shift in the
size and direction of the resulting synaptic change in the transgenic animals that favored
LTD. The regulation of this frequency-response is dependent on Ca
2+
-independent CaMKII
activity (Mayford et al., 1995). When the transgene is expressed at high levels in the lateral
amygdala and the striatum but not other forebrain structures, there is a deficit in fear
conditioning, an implicit memory task, that also is reversible. Thus, the CaMKII signaling
pathway is critical for both explicit and implicit memory storage, in a manner that is
independent of its potential role in development (Mayford et al. 1996). Mice expressing low
levels of the α CaMKII T268D transgene have facilitated low-frequency-induced LTP,
whereas mice with high levels of transgene expression have a deficit in this form of plasticity.
Behavioral impairments in fear-conditioned memory and visible water maze correlate with
the level of α CaMKII T268D expression. Mice with high levels of α CaMKII T268D have
reversible, compensatory changes in the expression of genes associated with inhibitory
neurotransmission (Bejar et al. 2002). These results indicate that the level of CaMKII activity
is important in the experience-dependent synaptic plasticity.
Mutation of Thr305, an inhibitory autophosphorylation site, to Asp (T305D) results in the
kinase becoming inactive because of inhibition of the binding to calmodulin. Mutation of
Thr305 to Val (T305V) results in the active form in the presence of Ca
2+
. It was demonstrated
that inhibitory autophosphorylation controls the association of CaMKII with the PSD,
synaptic plasticity, and learning using α CaMKII T305D mutant mice, (Elgersma et al.,
2002). Inhibitory autophosphorylation of CaMKII is also required for hippocampal
metaplasticity at the lateral perforant path-dentate granule cell synapse. Metaplasticity is
known as the higher-order form of plasticity. Metaplasticity was absent in knock-in mice
expressing the α CaMKII TT305/306VA mutant that cannot undergo inhibitory
phosphorylation, indicating that inhibitory autophosphorylation at Thr306/Thr306 is a key
mechanism for metaplasticity (Zhang et al., 2005).
3-4. Transgenic mice with CaMKII mRNA mutated at 3' UTR
α CaMKII mRNA in dendrites and the local synthesis of new α CaMII protein are
required for late-phase LTP (Miller et al., 2002). The dendritic localization signal of α
CaMKII mRNA is present in the 3' UTR. The signal is disrupted by deletion of the 3' UTR.
In this mutant mouse, the protein-coding region of α CaMKII is intact, but mRNA is
