title: GAD67-mediated GABA synthesis and signaling regulate inhibitory synaptic innervation in the visual cortex.
abstract: The development of GABAergic inhibitory circuits is shaped by neural activity, but the underlying mechanisms are unclear. Here, we demonstrate a novel function of GABA in regulating GABAergic innervation in the adolescent brain, when GABA is mainly known as an inhibitory transmitter. Conditional knockdown of the rate-limiting synthetic enzyme GAD67 in basket interneurons in adolescent visual cortex resulted in cell autonomous deficits in axon branching, perisomatic synapse formation around pyramidal neurons, and complexity of the innervation fields; the same manipulation had little influence on the subsequent maintenance of perisomatic synapses. These effects of GABA deficiency were rescued by suppressing GABA reuptake and by GABA receptor agonists. Germline knockdown of GAD67 but not GAD65 showed similar deficits, suggesting a specific role of GAD67 in the maturation of perisomatic innervation. Since intracellular GABA levels are modulated by neuronal activity, our results implicate GAD67-mediated GABA synthesis in activity-dependent regulation of inhibitory innervation patterns.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Bidisha
authors.initials: B
authors.lastname: Chattopadhyaya
authors.forename: Graziella
authors.initials: G
authors.lastname: Di Cristo
authors.forename: Cai Zhi
authors.initials: CZ
authors.lastname: Wu
authors.forename: Graham
authors.initials: G
authors.lastname: Knott
authors.forename: Sandra
authors.initials: S
authors.lastname: Kuhlman
authors.forename: Yu
authors.initials: Y
authors.lastname: Fu
authors.forename: Richard D
authors.initials: RD
authors.lastname: Palmiter
authors.forename: Z Josh
authors.initials: ZJ
authors.lastname: Huang
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000502:physiology*; D009474:Neurons / Q000145:classification / Q000166:cytology / Q000502:physiology; D009924:Organ Culture Techniques; D010320:Parvalbumins / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014793:Visual Cortex / Q000166:cytology* / Q000378:metabolism; D014795:Visual Pathways / Q000166:cytology / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D007527:Isoenzymes; D010320:Parvalbumins; D049452:Green Fluorescent Proteins; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D010751:Phosphopyruvate Hydratase