RRC ID 45572
Author Han B, Bellemer A, Koelle MR.
Title An evolutionarily conserved switch in response to GABA affects development and behavior of the locomotor circuit of Caenorhabditis elegans.
Journal Genetics
Abstract The neurotransmitter gamma-aminobutyric acid (GABA) is depolarizing in the developing vertebrate brain, but in older animals switches to hyperpolarizing and becomes the major inhibitory neurotransmitter in adults. We discovered a similar developmental switch in GABA response in Caenorhabditis elegans and have genetically analyzed its mechanism and function in a well-defined circuit. Worm GABA neurons innervate body wall muscles to control locomotion. Activation of GABAA receptors with their agonist muscimol in newly hatched first larval (L1) stage animals excites muscle contraction and thus is depolarizing. At the mid-L1 stage, as the GABAergic neurons rewire onto their mature muscle targets, muscimol shifts to relaxing muscles and thus has switched to hyperpolarizing. This muscimol response switch depends on chloride transporters in the muscles analogous to those that control GABA response in mammalian neurons: the chloride accumulator sodium-potassium-chloride-cotransporter-1 (NKCC-1) is required for the early depolarizing muscimol response, while the two chloride extruders potassium-chloride-cotransporter-2 (KCC-2) and anion-bicarbonate-transporter-1 (ABTS-1) are required for the later hyperpolarizing response. Using mutations that disrupt GABA signaling, we found that neural circuit development still proceeds to completion but with an ∼6-hr delay. Using optogenetic activation of GABAergic neurons, we found that endogenous GABAA signaling in early L1 animals, although presumably depolarizing, does not cause an excitatory response. Thus a developmental depolarizing-to-hyperpolarizing shift is an ancient conserved feature of GABA signaling, but existing theories for why this shift occurs appear inadequate to explain its function upon rigorous genetic analysis of a well-defined neural circuit.
Volume 199(4)
Pages 1159-72
Published 2015-4-1
DOI 10.1534/genetics.114.173963
PII genetics.114.173963
PMID 25644702
PMC PMC4391577
MeSH Animals Anion Transport Proteins / genetics Anion Transport Proteins / metabolism Caenorhabditis elegans / growth & development Caenorhabditis elegans / metabolism* Caenorhabditis elegans / physiology Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism GABA-A Receptor Agonists / pharmacology GABAergic Neurons / drug effects GABAergic Neurons / metabolism* GABAergic Neurons / physiology Locomotion* Membrane Potentials Muscimol / pharmacology Mutation Receptors, GABA-A / metabolism* Solute Carrier Family 12, Member 2 / genetics Solute Carrier Family 12, Member 2 / metabolism Symporters / genetics Symporters / metabolism Synaptic Transmission gamma-Aminobutyric Acid / metabolism*
IF 4.015
Times Cited 8
C.elegans tm1406 tm1165