title: Early formation of GABAergic synapses governs the development of adult-born neurons in the olfactory bulb.
abstract: In mammals, olfactory bulb granule cells (GCs) are generated throughout life in the subventricular zone. GABAergic inputs onto newborn neurons likely regulate their maturation, but the details of this process remain still elusive. Here, we investigated the differentiation, synaptic integration, and survival of adult-born GCs when their afferent GABAergic inputs are challenged by conditional gene targeting. Migrating GC precursors were targeted with Cre-eGFP-expressing lentiviral vectors in mice with a floxed gene encoding the GABA(A) receptor α2-subunit (i.e., Gabra2). Ablation of the α2-subunit did not affect GC survival but dramatically delayed their maturation. We found a reduction in postsynaptic α2-subunit and gephyrin clusters accompanied by a decrease in the frequency and amplitude of GABAergic postsynaptic currents beginning ∼14 d post-injection (dpi). In addition, mutant cells exhibited altered dendritic branching and spine density. Spine loss appeared with mislocation of glutamatergic synapses on dendritic shafts and a reduction of spontaneous glutamatergic postsynaptic currents, underscoring the relevance of afferent GABAergic transmission for a proper synaptic integration of newborn GCs. To test the role of GABAergic signaling during much early stages of GC maturation, we used a genetic strategy to selectively inactivate Gabra2 in precursor cells of the subventricular zone. In these mice, labeling of newborn GCs with eGFP lentiviruses revealed similar morphological alterations as seen on delayed Gabra2 inactivation in migrating neuroblasts, with reduced dendritic branching and spine density at 7 dpi. Collectively, these results emphasize the critical role of GABAergic synaptic signaling for structural maturation of adult-born GCs and formation of glutamatergic synapses.
authors: Department of Anatomy, Pharmacology, and Forensic Medicine and National Institute of Neuroscience-Italy, University of Turin, I-10126 Turin, Italy.
authors: Marta
authors: M
authors: Pallotto
authors: Antoine
authors: A
authors: Nissant
authors: Jean-Marc
authors: JM
authors: Fritschy
authors: Uwe
authors: U
authors: Rudolph
authors: Marco
authors: M
authors: Sassoè-Pognetto
authors: Patrizia
authors: P
authors: Panzanelli
authors: Pierre-Marie
authors: PM
authors: Lledo
mesh_terms: D053687:Adult Stem Cells / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D019540:Area Under Curve; D002352:Carrier Proteins / Q000378:metabolism; D003712:Dendrites / Q000502:physiology; D004558:Electric Stimulation; D027341:Excitatory Amino Acid Transporter 1 / Q000235:genetics; D005625:Frontal Lobe / Q000166:cytology / Q000502:physiology; D059330:GABAergic Neurons / Q000502:physiology*; D005786:Gene Expression Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006540:Herbicides / Q000633:toxicity; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000235:genetics; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D016253:Microscopy, Immunoelectron; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D009570:Nitriles / Q000633:toxicity; D009812:Odorants; D009830:Olfactory Bulb / Q000166:cytology* / Q000187:drug effects / Q000293:injuries; D018408:Patch-Clamp Techniques; D018079:Receptors, GABA / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics; D012683:Sensory Deprivation / Q000502:physiology; D013569:Synapses / Q000235:genetics / Q000502:physiology* / Q000648:ultrastructure; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; D027341:Excitatory Amino Acid Transporter 1; C493920:Gabra2 protein, mouse; D006540:Herbicides; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009570:Nitriles; D018079:Receptors, GABA; D011963:Receptors, GABA-A; C485184:enhanced green fluorescent protein; C073441:gephyrin; D013629:Tamoxifen; D049452:Green Fluorescent Proteins; C045073:Cre recombinase; D019426:Integrases; C055869:dichlobanil