title: Spatiotemporal specificity of GABAA receptor-mediated regulation of adult hippocampal neurogenesis.
abstract: GABAergic transmission regulates adult neurogenesis by exerting negative feedback on cell proliferation and enabling dendrite formation and outgrowth. Further, GABAergic synapses target differentiating dentate gyrus granule cells prior to formation of glutamatergic connections. GABA(A) receptors (GABA(A) Rs) mediating tonic (extrasynaptic) and phasic (synaptic) transmission are molecularly and functionally distinct, but their specific role in regulating adult neurogenesis is unknown. Using global and single-cell targeted gene deletion of subunits contributing to the assembly of GABA(A) Rs mediating tonic (α4, δ) or phasic (α2) GABAergic transmission, we demonstrate here in the dentate gyrus of adult mice that GABA(A) Rs containing α4, but not δ, subunits mediate GABAergic effects on cell proliferation, initial migration and early dendritic development. In contrast, α2-GABA(A) Rs cell-autonomously signal to control positioning of newborn neurons and regulate late maturation of their dendritic tree. In particular, we observed pruning of distal dendrites in immature granule cells lacking the α2 subunit. This alteration could be prevented by pharmacological inhibition of thrombospondin signaling with chronic gabapentin treatment, shown previously to reduce glutamatergic synaptogenesis. These observations point to homeostatic regulation of inhibitory and excitatory inputs onto newborn granule cells under the control of α2-GABA(A) Rs. Taken together, the availability of distinct GABA(A) R subtypes provides a molecular mechanism endowing spatiotemporal specificity to GABAergic control of neuronal maturation in adult brain.
authors: Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
authors: Venceslas
authors: V
authors: Duveau
authors: Simon
authors: S
authors: Laustela
authors: Lydia
authors: L
authors: Barth
authors: Francesca
authors: F
authors: Gianolini
authors: Kaspar E
authors: KE
authors: Vogt
authors: Ruth
authors: R
authors: Keist
authors: Dev
authors: D
authors: Chandra
authors: Gregg E
authors: GE
authors: Homanics
authors: Uwe
authors: U
authors: Rudolph
authors: Jean-Marc
authors: JM
authors: Fritschy
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D018891:Dentate Gyrus / Q000166:cytology / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D021122:Protein Subunits; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: C493920:Gabra2 protein, mouse; C546261:Gabra4 protein, mouse; D021122:Protein Subunits; D011963:Receptors, GABA-A