Developmental restoration of LTP deficits in heterozygous CaMKII{alpha} ko mice

The Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) is a major mediator of long-term potentiation (LTP) and depression (LTD), two opposing forms of synaptic plasticity underlying learning, memory and cognition. The heterozygous CaMKIIα isoform ko (CaMKIIα^+/-) mice have a schizophrenia-related phenotype, including impaired working memory. Here, we examined synaptic strength and plasticity in two brain areas implicated in working memory, hippocampus CA1 and medial prefrontal cortex (mPFC). Young CaMKIIα^+/- mice (postnatal day 12-16; corresponding to a developmental stage well before schizophrenia manifestation in humans) showed impaired hippocampal CA1 LTP. However, this LTP impairment normalized over development and was no longer detected in older CaMKIIα^+/- mice (postnatal week 9-11; corresponding to young adults). By contrast, the CaMKIIα^+/- mice failed to show the developmental increase of basal synaptic transmission in the CA1 seen in wild type mice, resulting in impaired basal synaptic transmission in the older CaMKIIα^+/- mice. Other electrophysiological parameters were normal, including mPFC basal transmission, LTP and paired pulse facilitation, as well as CA1 LTD, depotentiation, and paired-pulse facilitation at either age tested. Hippocampal CaMKIIα levels were ~60% of WT in both the older CaMKIIα^+/- mice and in the younger WT mice, resulting in ~30% of adult WT expression in the younger CaMKIIα^+/- mice; levels in frontal cortex were the same as in hippocampus. Thus, in young mice, ~30% of adult CaMKIIα expression is sufficient for normal LTD and depotentiation, while normal LTP requires higher levels, with ~60% of CaMKIIα expression sufficient for normal LTP in adult mice.

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