Pharmacogenetic analysis reveals a post-developmental role for Rac GTPases in Caenorhabditis elegans GABAergic neurotransmission.
The nerve-cell cytoskeleton is essential for the regulation of intrinsic neuronal activity. For example, neuronal migration defects are associated with microtubule regulators, such as LIS1 and dynein, as well as with actin regulators, including Rac GTPases and integrins, and have been thought to underlie epileptic seizures in patients with cortical malformations. However, it is plausible that post-developmental functions of specific cytoskeletal regulators contribute to the more transient nature of aberrant neuronal activity and could be masked by developmental anomalies. Accordingly, our previous results have illuminated functional roles, distinct from developmental contributions, for Caenorhabditis elegans orthologs of LIS1 and dynein in GABAergic synaptic vesicle transport. Here, we report that C. elegans with function-altering mutations in canonical Rac GTPase-signaling-pathway members demonstrated a robust behavioral response to a GABA(A) receptor antagonist, pentylenetetrazole. Rac mutants also exhibited hypersensitivity to an acetylcholinesterase inhibitor, aldicarb, uncovering deficiencies in inhibitory neurotransmission. RNA interference targeting Rac hypomorphs revealed synergistic interactions between the dynein motor complex and some, but not all, members of Rac-signaling pathways. These genetic interactions are consistent with putative Rac-dependent regulation of actin and microtubule networks and suggest that some cytoskeletal regulators cooperate to uniquely govern neuronal synchrony through dynein-mediated GABAergic vesicle transport in C. elegans.
Departments of Neurobiology and Neurology and Center for Neurodegeneration and Experimental Therapeutics, University of Alabama, Birmingham, Alabama 35294, USA.
Cody J
CJ
Locke
Bwarenaba B
BB
Kautu
Kalen P
KP
Berry
S Kyle
SK
Lee
Kim A
KA
Caldwell
Guy A
GA
Caldwell
D000448:Aldicarb / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000235:genetics* / Q000254:growth & development / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004398:Dyneins / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D007814:Larva / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000502:physiology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D010433:Pentylenetetrazole / Q000494:pharmacology; D010597:Pharmacogenetics; D034622:RNA Interference; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000235:genetics*; D013572:Synaptic Vesicles / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
D029742:Caenorhabditis elegans Proteins; D016023:Integrins; D008869:Microtubule-Associated Proteins; C513193:lis-1 protein, C elegans; D005680:gamma-Aminobutyric Acid; D000448:Aldicarb; D004398:Dyneins; D020744:rac GTP-Binding Proteins; D010433:Pentylenetetrazole