Assessing roles for autism-linked epigenetic factors in activity-dependent synapse elimination

  • Awarded: 2018
  • Award Type: Pilot
  • Award #: 575147

Sensory experience refines cortical circuits through activity-dependent stabilization and elimination of excitatory synaptic connections. As cortical circuits develop, there is an overproduction of excitatory synapses which are then pruned during childhood and adolescence. Accumulating evidence in humans and mouse models implicates alterations in synapse elimination or pruning in autism spectrum disorder (ASD). Little is known of the molecular mechanisms by which experience and experience-driven neural activity patterns eliminate synapses and the role played by ASD risk genes.

Kimberly Huber, Tae-Kyung Kim and others have shown that experience and neural activity trigger synapse elimination through the regulation of transcriptional control. Recent exome sequencing in individuals with ASD has identified mutations in genes whose protein products mediate activity-regulated transcriptional and chromatin regulation in neurons including: the CHD family of chromatin remodelers, the CBP/p300 histone acteyltransferases (HAT), BRD4, the acetylated histone reader and the Kmt2 family of histone H3 lysine 4 (H3K4) methyltransferases. It is hypothesized that these ASD-linked epigenetic factors regulate experience- and activity-dependent synapse elimination through precise control of activity-regulated gene networks.

To test this hypothesis, Huber and Kim plan to: 1) determine the functional requirement for ASD-linked epigenetic factors in activity-induced synapse elimination using mouse model systems and 2) identify the gene regulatory networks that are susceptible to altered activity of the ASD-linked epigenetic regulators at a single cell level. These studies are expected to determine the role of ASD-linked genes and regulatory pathways in activity-regulated circuit refinement and may identify new therapeutic targets for ASD.

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