Identifying mRNAs associated with a synaptogenic calcium-mediated pathway

Prof. Brian Ackley, Department of Molecular Biosciences
University of Kansas

Project dates: 2012-2015

Mentor: Erik Lundquist

Voltage-gated calcium channels (VGCCs) are the engines that drive the synapse. They are required for vesicle exocytosis, and it is now clear that these molecules are critically important to the dynamics of formation, maintenance, adaption and elimination that underlie changes in neural networks. Therefore, as we study these molecules and their mode of action, we will gain a much clearer understanding of the basic assembly of the nervous system. VGCCs have been linked to human diseases and disorders, most closely to epilepsy. In epileptic conditions excessive neural activity could result in structural changes in the brain. Also, treatment with anti-epilepsy drugs (AEDs) that inhibit VGCCs and/or activity could have detrimental effects on memory formation. In fact, epilepsy is commonly co-morbid with cognitive and psychiatric disorders, and AED treatment has been linked to poor cognitive function. We have identified genetic pathways that separate neural transmission and the facilitation of synapse formation downstream of VGCC activity.

Here our goal is to further the understanding of how these proteins contribute to neuronal development. Using animals that have mutations that inactivate or hyperactive synaptic VGCCs we will obtain transcriptome profiles to identify genes that are transcriptionally regulated by VGCC functional status. We will then target those genes for knockdown by RNAi to find molecules that contribute to VGCC-dependent synapse addition. Finally we will seek to visualize how calcium may be dynamic during times when synapses are being modified during development to correlate intracellular levels of calcium with specific changes in synapses. The organization of the C. elegans neuromuscular system provides a powerful genetic and cell biological model to study development. The primary motorneurons have many similarities to vertebrate CNS neurons, which are more difficult to study in vivo. C elegans may provide important insights into the mechanisms that underlie the formation and spacing of these types of synapses in vivo.

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