An RNAi screen identifies genes that regulate GABA synapses.
GABA synapses play a critical role in many aspects of circuit development and function. For example, conditions that perturb GABA transmission have been implicated in epilepsy. To identify genes that regulate GABA transmission, we performed an RNAi screen for genes whose inactivation increases the activity of C. elegans body muscles, which receive direct input from GABAergic motor neurons. We identified 90 genes, 21 of which were previously implicated in seizure syndromes, suggesting that this screen has effectively identified candidate genes for epilepsy. Electrophysiological recordings and imaging of excitatory and inhibitory synapses indicate that several genes alter muscle activity by selectively regulating GABA transmission. In particular, we identify two humoral pathways and several protein kinases that modulate GABA transmission but have little effect on excitatory transmission at cholinergic neuromuscular junctions. Our data suggest these conserved genes are components of signaling pathways that regulate GABA transmission and consequently may play a role in epilepsy and other cognitive or psychiatric disorders.
Vashlishan
Amy B
AB
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Madison
Jon M
JM
Dybbs
Mike
M
Bai
Jihong
J
Sieburth
Derek
D
Ch'ng
Queelim
Q
Tavazoie
Masoud
M
Kaplan
Joshua M
JM
D000109:Acetylcholine / Q000502:physiology; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D004703:Endocrine System / Q000502:physiology; D004827:Epilepsy / Q000235:genetics / Q000503:physiopathology; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics / Q000502:physiology; D005820:Genetic Testing / Q000379:methods*; D053444:Inhibitory Postsynaptic Potentials / Q000235:genetics / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D009046:Motor Neurons / Q000502:physiology; D009068:Movement / Q000502:physiology; D009132:Muscles / Q000502:physiology; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D018079:Receptors, GABA / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D029742:Caenorhabditis elegans Proteins; D009478:Neuropeptide Y; D018079:Receptors, GABA; D016212:Transforming Growth Factor beta; D005680:gamma-Aminobutyric Acid; D020928:Mitogen-Activated Protein Kinases; D000109:Acetylcholine