Novel insights into neuronal CAMK2 function

CAMK2A and CAMK2B are amongst the most abundant proteins in the brain and crucial for learning and memory. Recently, individuals with severe intellectual disability carrying mutations in the genes coding for CAMK2A or CAMK2B have been identified, emphasizing the role of CAMK2 in learning and memory in human. In this thesis the individual as well as the shared role of CAMK2A and CAMK2B in learning and memory is investigated using conditional knockout mouse models, where CAMK2A or CAMK2B can be deleted with spatial and/or temporal precision. First, we tested the spatiotemporal requirement of CAMK2A for spatial learning and plasticity, showing the necessity for CAMK2A expression at the moment of learning and LTP induction. Second, we tested the spatiotemporal requirement of CAMK2B in locomotion, finding an important role for CAMK2B during development. Third, we assessed the shared role of CAMK2A and CAMK2B and found that not only absence, but also loss of kinase activity of both proteins simultaneously leads to premature death. Finally, we found that at the level of a single neuron, loss of both CAMK2A and CAMK2B results in changes in excitability and loss of neuronal input. Together, this thesis further elucidates the function of CAMK2 at the behavioural level, the network level and the single cell level. Understanding these functions will provide new insights for finding therapies for patients with intellectual disability caused by mutations in one of the CAMK2 genes

CAMK2-Dependent Signaling in Neurons Is Essential for Survival

Ca2+/calmodulin-dependent protein kinase II (CAMK2) is a key player in synaptic plasticity and memory formation. Mutations in Camk2a or Camk2b cause intellectual disability in humans, and severe plasticity and learning deficits in mice, indicating unique functions for each isoform. However, considering the high homology between CAMK2A and CAMK2B, it is conceivable that for critical functions, one isoform compensates for the absence of the other, and that the full functional spectrum of neuronal CAMK2 remains to be revealed.Here we show that germline as well as adult deletion of both CAMK2 isoforms in male or female mice is lethal. Moreover, Ca2+-dependent activity as well as autonomous activity of CAMK2 is essential for survival. Loss of both CAMK2 isoforms abolished LTP, whereas synaptic transmission remained intact. The double-mutants showed no gross morphological changes of the brain, and in contrast to the long-considered role for CAMK2 in the structural organization of the postsynaptic density (PSD), deletion of both CAMK2 isoforms did not affect the biochemical composition of the PSD. Together, these results reveal an essential role for CAMK2 signaling in early postnatal development as well as the mature brain, and indicate that the full spectrum of CAMK2 requirements cannot be revealed in the single mutants because of partial overlappin

KNGF-standaard. Beweeginterventie oncologie

In 2008 heeft het Koninklijk Nederlands Genootschap voor Fysiotherapie (KNGF) de KNGF-beweegprogramma’s herzien; het warden de ‘Standaarden Beweeginterventies’, gericht op mensen met een chronische aandoening. Een dergelijke standaard stelt een voldoende competente fysiotherapeut in staat bij mensen met een chronische aandoening een actieve leefstijl te bevorderen en hun mate van fitheid te verhogen. Basis voor de herziening vormen de oorspronkelijk door TNO ontwikkelde beweegprogramma’s, van waaruit de tekst grondig is geactualiseerd. De gedetailleerde invulling van de programma’s in ‘kookboekstijl’ is niet opnieuw opgenomen. Gekozen is voor een actueel concept dat de fysiotherapeut de mogelijkheid biedt een ‘state-of-the-art’programma te ontwikkelen met respect voor de individuele patiënt en praktijkspecifieke randvoorwaarde

Temporal and region-specific requirements of αCaMKII in spatial and contextual learning

The α isoform of the calcium/calmodulin-dependent protein kinase II (αCaMKII) has been implicated extensively in molecular and cellular mechanisms underlying spatial and contextual learning in a wide variety of species. Germline deletion of Camk2a leads to severe deficits in spatial and contextual learning in mice. However, the temporal and region-specific requirements for αCaMKII have remained largely unexplored. Here, we generated conditional Camk2a mutants to examine the influence of spatially restricted and temporally controlled expression of αCaMKII. Forebrain-specific deletion of the Camk2a gene resulted in severe deficits in water maze and contextual fear learning, whereas mice with deletion restricted to the cerebellum learned normally. Furthermore, we found that temporally controlled deletion of the Camk2a gene in adult mice is as detrimental as germline deletion for learning and synaptic plasticity. Together, we confirm the requirement for αCaMKII in the forebrain, but not the cerebellum, in spatial and contextual learning. Moreover, we highlight the absolute requirement for intact αCaMKII expression at the time of learning