Activity-dependent splicing is crucial for learning and memory

Learning relies on neuronal plasticity through the dynamic modification of proteome repertoire. Among the mechanisms that trigger proteome remodeling, activity-dependent transcription and -translation programs have been shown to be essential for learning and memory. Yet, alternative splicing is the main driver of proteome diversification and its regulation emerges to dramatically impact the neuronal proteome upon stimulation. Surprisingly, its role in learning and memory remains largely unexplored. In this study, we show that the kinase CLK1, a pivotal regulator of alternative splicing, is regulated in response to multiple paradigms in vivo, notably after contextual fear conditioning. CLK1 is regulated through an unconventional mechanism that targets the maturation of its transcripts. In unstimulated conditions, Clk1 transcripts are stored as immature forms that retained select introns. Upon activity, those introns are excised through splicing reaction allowing its complete maturation and the subsequent synthesis of CLK1 proteins.To test the function of CLK1 regulation, we have developed a novel strategy - leveraging a new generation of antisense oligonucleotides – to block Clk1 intron excision. Using this strategy, we found that Clk1 activity-dependent intron excision is crucial for the formation of contextual fear memory. We are now investigating what are the alternative splicing programs controlled by CLK1 induction. In summary, our study unveils the pivotal role of the alternative splicing regulator CLK1 and its activity-dependent regulation in learning and memory.