The long-term goal of this project is to understand the molecular pathways that regulate neural circuit and electrical synapse formation in vivo. Neural circuits are organized by synapses, which are specialized sites of adhesion and communication whose patterns and properties form the basis of all of brain function. Synapses can be either chemical, where signals are transmitted via neurotransmitter release and reception, or electrical, where signals pass directly through gap junctions between neurons. Of these, the chemical synapse has received more attention in recent years;however growing evidence suggests that electrical synapses are widespread in the brain where they modulate neural circuits from sensory perception to cortical processing to motor output. Underlying neural circuit and synapse formation are genetic mechanisms ensuring that neurons select appropriate targets and recruit the complex synaptic machinery to the sites of contact. However, the genes that regulate these processes are not well understood, especially in regard to electrical synapse formation. This proposal will use the zebrafish Mauthner (M) circuit as a model for understanding the genetic basis of neural circuit wiring and electrical synapse formation. The well-characterized M circuit is simple and accessible, and is necessary for a stereotypical escape response behavior. These properties, in conjunction with genetic tools that specifically mark the cells of the neural circuit and their stereotyped chemical and electrical synapses, provide a unique opportunity to investigate circuit wiring and to find mutations that affect electrical synaptogenesis. The goal of the research is to investigate the normal developmental steps that occur during M circuit wiring (Aim1), to identify mutations that specifically affect electrical synapse formation and investigate their defects at the cell-biological and functional levels (Aim2), and to identify the underlying mutated genes providing the first insight into the molecular mechanisms that build electrical synapses (Aim3). Such knowledge is critical given that defects in synapse development or function are associated with a number of neurodevelopmental disorders, including autism and epilepsy, and also age-related diseases, such as Alzheimers. A fundamental understanding of how synapses are built is essential for improved detection of disease and for guiding the development of therapies.
The central nervous system, as Carl Sagan would say, contains billions and billions of neurons that are organized into connected circuits that allow for the transfer and processing of information, ultimately leading to perception, thought, and behavior. It is clear that the brain is not just a jumble of wires randomly linked to one another, but instead very specific and reproducible circuits are created and defects in the genes underlying their development lead to a number of diseases such as autism and epilepsy. This study proposes to investigate how genes regulate the creation of neuronal circuits, giving insight into this fundamental process and knowledge that is necessary to guide future therapeutic work that attempts to fix diseased brains.
| Miller, Adam C; Voelker, Lisa H; Shah, Arish N et al. (2015) Neurobeachin is required postsynaptically for electrical and chemical synapse formation. Curr Biol 25:16-28 |
| Miller, Adam C; Obholzer, Nikolaus D; Shah, Arish N et al. (2013) RNA-seq-based mapping and candidate identification of mutations from forward genetic screens. Genome Res 23:679-86 |
