Biology Reference
In-Depth Information
either for the induction or for the expression of plasticity (Glazewski et al., 1996).
However,
seizure susceptibility is increased in α CaMKII null mutant mice (Burtler et al., 1995). Thus,
interest has been directed torward the molecular mechanism of learning and memory through
the action of this kinase.
In the cerebellum of the α CaMKII null mutant mouse, a long-term depression (LTD)
protocol results in only transient depression and in robust potentiation in adults. This suggests
that the function of α CaMKII in parallel fiber-Purkinje cell plasticity is opposite to its
function at excitatory hippocampal and cortical synapses. α CaMKII null mutant mice also
show impaired gain-increase adaptation of both the vestibular ocular reflex and optokinetic
reflex (Hansel et al., 2006).
3-2. Overexpression of CaMKII in mice and rats
When α CaMKII was overexpressed in the rat hippocampus using an adeno-associated
viral vector, the transgenic rat exhibited improved performance in a water maze task, but no
change in locomotor activity and exploratory behavior in an open field task, indicating that α
CaMKII plays a role in spatial or explicit memory storage (Poulsen et al., 2007).
Using targeted chemical-genetic engineering, an
in vivo
conditional protein knockout
and/or manipulation technology was developed (Wang et al., 2003). The α CaMKII-F86G
mutant kinase is created based on the specific interaction interface between a modified
protein domain and sensitized inhibitors. The mutant enzyme accepts ATP normally, but has
highly sensitive to a specific inhibitor. The transgenic mice show a significant elevation in
both Ca
2+
-dependent and Ca
2+
-independent CaMKII activity. CaMKII overexpression alters
frequency-plasticity responses in the hippocampal Schaffer-collateral pathway. This effect is
blocked by the CaMKII inhibitor. A precise level of CaMKII reactivation is essential for the
consolidation of long-term memories in the brain (Wang et al., 2003).
Similarly, the β CaMKII-F90G mutant was created by targeted chemical-genetic
engineering to investigate the functional difference between α CaMKII and β CaMKII
in vivo
(Cho et al., 2007). Experiments with the transgenic mice showed that β CaMKII activity in
the dentate gyrus selectively impairs LTP in the dentate perforant path. The mice had normal
1-day memories, but were severely impaired in 10-day contextual fear memory, indicating
that the initial day is a critical time within the postlearning consolidation period and is highly
sensitive to change in β CaMKII (Cho et al., 2007).
3-3. Transgenic mice with CaMKII mutated at autophosphorylation sites
Autophosphorylation of α CaMKII at Thr 286 converts the kinase to a Ca
2+
-independent
enzyme. This Thr (T) residue is mutated to Ala (A), resulting in a deficiency of
autophosphorylation and activation, and to Asp (D), resulting in mimicking the autonomous
activity of the kinase autophosphorylated at Thr286. (The letter in the parenthesis indicates
the amino acid as one letter.) Ca
2+
-independent activity induced by autophosphorylation of α
CaMKII is essential for the induction and maintenance of LTP (Lisman et al., 2002). The
requirement of α CaMKII autophosphorylation for neocortical LTP and experience-
