title: Developmental restoration of LTP deficits in heterozygous CaMKIIα KO mice.
abstract: 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 days 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 weeks 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 (WT) 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.
authors.affiliation: Department of Pharmacology and Program in Neuroscience, University of Colorado Anschutz Medical Campus, Aurora, Colorado; and.
authors.forename: Dayton J
authors.initials: DJ
authors.lastname: Goodell
authors.affiliation: Department of Pharmacology and Program in Neuroscience, University of Colorado Anschutz Medical Campus, Aurora, Colorado; and.|Division of Pediatric Neurology, University of Colorado, School of Medicine, Children's Hospital Colorado, Aurora, Colorado.
authors.forename: Tim A
authors.initials: TA
authors.lastname: Benke
authors.affiliation: Department of Pharmacology and Program in Neuroscience, University of Colorado Anschutz Medical Campus, Aurora, Colorado; and ulli.bayer@ucdenver.edu.
authors.forename: K Ulrich
authors.initials: KU
authors.lastname: Bayer
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000172:deficiency* / Q000235:genetics; D002540:Cerebral Cortex / Q000201:enzymology / Q000254:growth & development*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000201:enzymology / Q000254:growth & development*; D017774:Long-Term Potentiation / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000502:physiology; D009924:Organ Culture Techniques
chemical_list: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: CaMKII; LTD; LTP; schizophrenia; synaptic transmission