Shaham, S. | Search bioRxiv

bioRxiv2018

Glutamate spillover in C. elegans triggers repetitive behavior through presynaptic activation of MGL-2/mGluR5

Glutamate is a major excitatory neurotransmitter, and impaired glutamate clearance following synaptic release promotes spillover, inducing extra-synaptic signaling. The effects of glutamate spillover on animal behavior and its neural correlates are poorly understood. We developed a glutamate spillover model in Caenorhabditis elegans by inactivating the conserved glial glutamate transporter GLT-1. GLT-1 loss drives aberrant repetitive locomotory reversal behavior through uncontrolled oscillatory release of glutamate onto AVA, a major interneuron governing reversals. Repetitive glutamate release and reversal behavior require the glutamate receptor MGL-2/mGluR5, expressed in RIM and other interneurons presynaptic to AVA. mgl-2 loss blocks oscillations and repetitive behavior; while RIM activation is sufficient to induce repetitive reversals in glt-1 mutants. Repetitive AVA firing and reversals require EGL-30/Gq, an mGluR5 effector. Our studies reveal that cyclic autocrine presynaptic activation drives repetitive reversals following glutamate spillover. That mammalian GLT1 and mGluR5 are implicated in pathological motor repetition suggests a common mechanism controlling repetitive behaviors.

neuroscience↗

bioRxiv2017

RAB-35 and ARF-6 GTPases Mediate Engulfment and Clearance Following Linker Cell-Type Death

Clearance of dying cells is essential for development and homeostasis. Conserved genes mediate apoptotic cell removal, but whether these genes also control non-apoptotic cell removal is a major open question. Linker cell-type death (LCD) is a prevalent non-apoptotic developmental cell death process with features conserved from C. elegans to vertebrates. Using microfluidics-based long-term in vivo imaging, we show that unlike apoptotic cells, the C. elegans linker cell, which dies by LCD, is competitively phagocytosed by two neighboring cells, resulting in cell splitting. Subsequent cell elimination does not require apoptotic engulfment genes. Rather, we find that RAB-35 GTPase is a key coordinator of competitive phagocytosis onset and linker cell degradation. RAB-35 binds CNT-1, an ARF-6 GTPase activating protein; removes ARF-6, a degradation inhibitor, from phagosome membranes; and recruits RAB-5 and RAB-7 GTPases for phagolysosome maturation. We propose that RAB-35 and ARF-6 drive an evolutionarily conserved program eliminating cells dying by LCD.

cell biology↗