Branch point strength controls species-specificCAMK2Balternative splicing and regulates LTP

Abstract

Regulation and functionality of species-specific alternative splicing has remained enigmatic to the present date. Calcium/calmodulin-dependent protein kinase IIβ (CaMKIIβ) is expressed in several splice variants and plays a key role in learning and memory. Here, we identify and characterize several primate-specificCAMK2Bsplice isoforms, which show altered kinetic properties and changes in substrate specificity. Furthermore, we demonstrate that primate-specificCAMK2Balternative splicing is achieved through branch point weakening during evolution. We show that reducing branch point and splice site strengths during evolution globally renders constitutive exons alternative, thus providing novel mechanistic insight intocis-directed species-specific alternative splicing regulation. Using CRISPR/Cas9, we introduce a weaker, human branch point sequence into the mouse genome, resulting in strongly alteredCamk2bsplicing in the brains of mutant mice. We observe a strong impairment of long-term potentiation in CA3-CA1 synapses of mutant mice, thus connecting branch point–controlledCAMK2Balternative splicing with a fundamental function in learning and memory.