1. CAMK2-Dependent Signaling in Neurons Is Essential for Survival
- Author
-
Martijn J. Kool, Jeroen Demmers, Enzo Nio, Karel Bezstarosti, Gabriëlle H.S. Buitendijk, Mehrnoush Aghadavoud Jolfaei, Jolet E. van de Bree, Martina Proietti Onori, Geeske M. van Woerden, Minetta Elgersma-Hooisma, Ype Elgersma, Nils Z. Borgesius, Neurosciences, and Biochemistry
- Subjects
Male ,0301 basic medicine ,Gene isoform ,Neurogenesis ,Long-Term Potentiation ,Mutant ,Hippocampus ,Neurotransmission ,Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,CAMK2A ,Animals ,Germ-Line Mutation ,Research Articles ,Neurons ,General Neuroscience ,Brain ,Post-Synaptic Density ,Long-term potentiation ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,Synaptic plasticity ,Female ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,Postsynaptic density ,Gene Deletion ,030217 neurology & neurosurgery - Abstract
Ca(2+)/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, Ca(2+)-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 overlapping functions of CAMK2A and CAMK2B. SIGNIFICANCE STATEMENT CAMK2A and CAMK2B have been studied for over 30 years for their role in neuronal functioning. However, most studies were performed using single knock-out mice. Because the two isoforms show high homology with respect to structure and function, it is likely that some redundancy exists between the two isoforms, meaning that for critical functions CAMK2B compensates for the absence of CAMK2A and vice versa, leaving these functions to uncover. In this study, we generated Camk2a/Camk2b double-mutant mice, and observed that loss of CAMK2, as well as the loss of Ca(2+)-dependent and Ca(2+)-independent activity of CAMK2 is lethal. These results indicate that despite 30 years of research the full spectrum of CAMK2 functioning in neurons remains to be unraveled.
- Published
- 2019