TY - JOUR
T1 - Spatiotemporal specificity of GABAA receptor-mediated regulation of adult hippocampal neurogenesis
AU - Duveau, Venceslas
AU - Laustela, Simon
AU - Barth, Lydia
AU - Gianolini, Francesca
AU - Vogt, Kaspar E.
AU - Keist, Ruth
AU - Chandra, Dev
AU - Homanics, Gregg E.
AU - Rudolph, Uwe
AU - Fritschy, Jean Marc
PY - 2011/8
Y1 - 2011/8
N2 - 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. GABAA receptors (GABAARs) 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 GABAARs mediating tonic (α4, δ) or phasic (α2) GABAergic transmission, we demonstrate here in the dentate gyrus of adult mice that GABAARs containing α4, but not δ, subunits mediate GABAergic effects on cell proliferation, initial migration and early dendritic development. In contrast, α2-GABAARs 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-GABAARs. Taken together, the availability of distinct GABAAR subtypes provides a molecular mechanism endowing spatiotemporal specificity to GABAergic control of neuronal maturation in adult brain.
AB - 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. GABAA receptors (GABAARs) 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 GABAARs mediating tonic (α4, δ) or phasic (α2) GABAergic transmission, we demonstrate here in the dentate gyrus of adult mice that GABAARs containing α4, but not δ, subunits mediate GABAergic effects on cell proliferation, initial migration and early dendritic development. In contrast, α2-GABAARs 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-GABAARs. Taken together, the availability of distinct GABAAR subtypes provides a molecular mechanism endowing spatiotemporal specificity to GABAergic control of neuronal maturation in adult brain.
KW - BrdU
KW - Gabapentin
KW - Neural precursor cell
KW - Retroviral vector
KW - Synaptic homeostasis
UR - http://www.scopus.com/inward/record.url?scp=79960932708&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79960932708&partnerID=8YFLogxK
U2 - 10.1111/j.1460-9568.2011.07782.x
DO - 10.1111/j.1460-9568.2011.07782.x
M3 - Article
C2 - 21722213
AN - SCOPUS:79960932708
SN - 0953-816X
VL - 34
SP - 362
EP - 373
JO - European Journal of Neuroscience
JF - European Journal of Neuroscience
IS - 3
ER -