Gabrielle Rieckhof, Ph.D., 2000-2003

B.S. in Biology at Cornell Univ., 1987

Ph.D. in Neuroscience at Columbia, 1998

Gabrielle identified and characterized a novel role for calcium channels in synaptic wiring.  Voltage-gated calcium channels couple changes in membrane potential to cellular functions regulated by calcium, including neurotransmitter release and muscle contraction.  The Drosophila genome encodes three a-subunit calcium channel genes, including homologs of the mammalian T-type, L-type (Dmca1D), and N-type (Dmca1A) channels.  Gabrielle found that presynaptic N-type calcium channels not only control neurotransmitter release, but also regulate synaptic growth at the Drosophila neuromuscular junction.  In a screen for behavioral mutants that disrupt synaptic transmission, alleles of the N-type calcium channel locus were identified that caused synaptic undergrowth at the neuromuscular junction.  The underlying molecular defect in the most severe allele was identified as a neutralization of a charged residue in the third S4 voltage sensor.  RNAi reduction of N-type calcium channel expression also reduced synaptic growth.  Hypomorphic mutations in syntaxin-1A or n-synaptobrevin, which disrupt neurotransmitter release, did not affect synapse proliferation at the neuromuscular junction, suggesting calcium entry through presynaptic N-type calcium channels, not neurotransmitter release per se, is important for synaptic growth.  The reduced synapse proliferation in Dmca1A mutants is not due to increased synapse retraction, but instead reflects a role for calcium influx in synaptic growth mechanisms. Gabrielle’s findings suggest N-type channels participate in synaptic growth through signaling pathways that are distinct from those that mediate transmitter release.  Linking presynaptic voltage-gated calcium entry to downstream calcium-sensitive synaptic growth regulators may provide a direct activity-dependent mechanism for modifying synaptic strength.