Perturbations to Stimulus-Dependent Gene Activity Patterns in Neurodegenerative Disorders

Many of the enduring effects of experience, such as the formation of long-term memories, require the activation of new gene transcription programs in neurons immediately following the exposure to a stimulus. While disruptions in neuronal activity-dependent transcription programs manifest in neurodevelopmental disorders, emerging evidence suggests that activity-dependent transcription programs are also disrupted in progressive neurodegenerative disorders. In this chapter, we discuss how altered synapse-to-nucleus signaling dysregulates activity-dependent gene transcription programs in neurodegenerative disorders. We then present insights from epigenomic and chromatin interaction profiling studies, which reveal how stimulus-responsive gene activity states are rewired in neurodegenerative diseases and could underlie disease progression. Finally, we examine how recurrent DNA breaks at activity-dependent genes and age-related changes to DNA repair could lead to the progressive deterioration of neuronal functions.