title: Genetic elimination of GABAergic neurotransmission reveals two distinct pacemakers for spontaneous waves of activity in the developing mouse cortex.
abstract: Many structures of the mammalian CNS generate propagating waves of electrical activity early in development. These waves are essential to CNS development, mediating a variety of developmental processes, such as axonal outgrowth and pathfinding, synaptogenesis, and the maturation of ion channel and receptor properties. In the mouse cerebral cortex, waves of activity occur between embryonic day 18 and postnatal day 8 and originate in pacemaker circuits in the septal nucleus and the piriform cortex. Here we show that genetic knock-out of the major synthetic enzyme for GABA, GAD67, selectively eliminates the picrotoxin-sensitive fraction of these waves. The waves that remain in the GAD67 knock-out have a much higher probability of propagating into the dorsal neocortex, as do the picrotoxin-resistant fraction of waves in controls. Field potential recordings at the point of wave initiation reveal different electrical signatures for GABAergic and glutamatergic waves. These data indicate that: (1) there are separate GABAergic and glutamatergic pacemaker circuits within the piriform cortex, each of which can initiate waves of activity; (2) the glutamatergic pacemaker initiates waves that preferentially propagate into the neocortex; and (3) the initial appearance of the glutamatergic pacemaker does not require preceding GABAergic waves. In the absence of GAD67, the electrical activity underlying glutamatergic waves shows greatly increased tendency to burst, indicating that GABAergic inputs inhibit the glutamatergic pacemaker, even at stages when GABAergic pacemaker circuitry can itself initiate waves.
authors.affiliation: Department of Biology, Department of Bioengineering, and Department of Neurological Surgery, University of Washington, Seattle, Washington 98195, and Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington 98101.
authors.forename: Curtis R
authors.initials: CR
authors.lastname: Easton
authors.forename: Keiko
authors.initials: K
authors.lastname: Weir
authors.forename: Adina
authors.initials: A
authors.lastname: Scott
authors.forename: Samantha P
authors.initials: SP
authors.lastname: Moen
authors.forename: Zeke
authors.initials: Z
authors.lastname: Barger
authors.forename: Albert
authors.initials: A
authors.lastname: Folch
authors.forename: Robert F
authors.initials: RF
authors.lastname: Hevner
authors.forename: William J
authors.initials: WJ
authors.lastname: Moody
mesh_terms: D000818:Animals; D001683:Biological Clocks / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology*; D005260:Female; D005333:Fetus; D059330:GABAergic Neurons / Q000502:physiology*; D005968:Glutamate Decarboxylase / Q000235:genetics* / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019579:Neocortex / Q000196:embryology* / Q000502:physiology*; D009433:Neural Inhibition / Q000502:physiology; D009924:Organ Culture Techniques; D011247:Pregnancy; D020665:Septum of Brain / Q000196:embryology / Q000502:physiology; D009435:Synaptic Transmission / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000235:genetics / Q000378:metabolism*
chemical_list: D049452:Green Fluorescent Proteins; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1
keywords: GABA; activity-dependent development; pacemaker; piriform cortex; spontaneous activity