Adult Camk2a gene reinstatement restores the learning and plasticity deficits of Camk2a knockout mice.

With the recent findings that mutations in the gene encoding the α-subunit of calcium/calmodulin-dependent protein kinase II (CAMK2A) causes a neurodevelopmental disorder (NDD), it is of great therapeutic relevance to know if there exists a critical developmental time window in which CAMK2A needs to be expressed for normal brain development, or whether expression of the protein at later stages is still beneficial to restore normal functioning. To answer this question, we generated an inducible Camk2a mouse model, which allows us to express CAMK2A at any desired time. Here, we show that adult expression of CAMK2A rescues the behavioral and electrophysiological phenotypes seen in the Camk2a knock-out mice, including spatial and conditional learning and synaptic plasticity. These results suggest that CAMK2A does not play a critical irreversible role in neurodevelopment, which is of importance for future therapies to treat CAMK2A-dependent disorders.

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 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 Ca2+-dependent and Ca2+-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.