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bioRxiv · 10.1101/2022.06.07.494679

Bidirectional changes in excitability upon loss of both CAMK2A and CAMK2B.

Kool, M. J.·Bodde, H. E.·Elgersma, Y.·van Woerden, G.
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Abstract

The mammalian Ca2+/calmodulin-dependent protein kinase II (CAMK2) family consists of 4 different CAMK2 genes, encoding CAMK2A, CAMK2B, CAMK2D and CAMK2G, which have high structural homology. CAMK2A and CAMK2B are abundantly expressed in the brain; they play a unique role in proper neuronal functioning, since both CAMK2A and CAMK2B knockout mice show several behavioural and cellular phenotypes. However, our recent finding that deletion of both CAMK2A and CAMK2B is lethal indicates that they show redundancy and that the full spectrum of CAMK2 function in neurons remains to be uncovered. For example, it still remains unclear which overlapping functions are present at a single cell level in neuronal transmission and excitability. In order to get more insight into the full spectrum of CAMK2 functions in neurons, we performed whole-cell patch clamp experiments in inducible Camk2a/Camk2b double knockout mice, as well as the CAMK2A and CAMK2B knockout mice. We found that whereas deletion of only CAMK2A or CAMK2B did not change excitability, simultaneous deletion of CAMK2A and CAMK2B resulted in a decrease in excitability 10 days after deletion in CA1 pyramidal neurons, which reversed to increased excitability 21 days after deletion. Additionally, loss of both CAMK2A and CAMK2B resulted in a decreased frequency of both miniature excitatory and inhibitory postsynaptic currents (mEPSC and mIPSC) 21 days after deletion, but not 10 days after deletion, an effect not seen in the single mutants. Our results indicate that CAMK2 is critically important to maintain normal excitability of hippocampal CA1 pyramidal cells, as well as normal inhibitory and excitatory synaptic transmission. Together, these results lead to new insights in how CAMK2 regulates normal neuronal function and highlight the importance of having both CAMK2A and CAMK2B expressed in high levels in the brain.

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Kool, M. J., Bodde, H. E., Elgersma, Y., van Woerden, G.. 2022-06-09. Bidirectional changes in excitability upon loss of both CAMK2A and CAMK2B.. https://doi.org/10.1101/2022.06.07.494679

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