The formation of sensory cortical circuits in the mammalian brain is largely completed at the onset of sensation, with individual cortical neurons exhibiting specific and selective response properties that undergo only minor refinement thereafter. Before sensation, all sensory systems exhibit spontaneous patterned activity that propagates through ascending sensory pathways to primary cortical areas. The structure and spatio-temporal dynamics of such spontaneous patterned activity are thought to have a major impact on cortical wiring.

Simultaneously, with spontaneous activity, transcriptional programs unfold that specify cortical cell types, steer their anatomical projections, and may instruct wiring specificity. Alternative mRNA splicing has emerged as a central post-transcriptional mechanism for expanding the molecular codes for neuronal wiring and synapse specification. Moreover, alterations in alternative splicing programs have been linked to neurodevelopmental disorders, in particular autism.

It is unknown how spontaneous activity, transcriptional and – in particular – alternative splicing programs interact to drive neuronal wiring in cortex. In this project, we will use the mouse visual cortex as a model system to address these fundamental questions. In Aim 1, we will use in vivo two-photon calcium imaging of individual neurons to map developmental emergence of spontaneous patterned activity and will correlate spontaneous activity patterns to cell type-specific transcript isoform programs. In Aim 2, we will shift patterns of spontaneous activity in the retina and will develop novel genetic sparse marking approaches to explore the impact of patterned activity on transcript isoform programs and neuronal wiring. In Aim 3, we will uncover mechanisms underlying neuronal activity-dependent alternative splicing regulation by advancing novel genetically targeted in vivo methods for dissecting RNA-protein interactions.

Together these experiments will illuminate how spontaneous activity in developing sensory systems instructs alternative splicing programs and will advance our understanding of how developmental processes mediate the acquisition of functional specificity in mature cortical networks.  Finally, the results will have a profound impact on the interpretation of alternative splicing and network level defects underlying neurodevelopmental diseases.