Neuronal circuits in the brain constantly process internal and external stimuli that enable higher organisms to learn and adapt to their environment. Understanding the molecular mechanisms linking the resultant neuronal activity and modifications in cellular networks represents a major challenge for neurobiologists. Activity-dependent alternative splicing has recently emerged as a mechanism for the dynamic modification of neuronal function. However, the extents of such neuronal alternative splicing programs are poorly understood.

Regulation of intron retention, an underestimated class of alternative splicing so far, represents an appealing novel pathways involved in activity dependant-synaptic plasticity. Indeed, it is an alternative tempting hypothesis that some retained introns could be excised in response to cellular stimuli, thus, providing a novel mechanism for rapid signalling-dependent shifts in the cellular transcriptome.

The goal of this proposal is to use a combination of genome-wide approaches to (1) map robust intron retention events in primary neurons, (2) to quantify dynamics of retained intron-containing RNAs in response to neuronal activity, and (3) to explore expression of proteins derived from transcripts that exhibit intron retention. Ultimately, we will test the hypothesis that intron retention represents a novel mechanism to regulate spatiotemporal dynamics of the neuronal proteome in response to stimuli.