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. 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.

GABA suppresses neurogenesis in the adult hippocampus through GABAB receptors

“…In the adult hippocampus, ionotropic GABA A receptors have been reported to decrease cell proliferation (Duveau et al, 2011;Song et al, 2012). It remains unclear whether differential regulation occurs at the level of intermediate progenitors and neuroblasts (Tozuka et al, 2005;Ge et al, 2006) versus NSCs Song et al, 2012).…”

“…GABA can promote or suppress proliferation depending on developmental stage, brain region and the fate of distinct progenitor populations (Haydar et al, 2000;Liu et al, 2005;Duveau et al, 2011). In the adult hippocampus, ionotropic GABA A receptors have been reported to decrease cell proliferation (Duveau et al, 2011;Song et al, 2012).…”

“…Neurotransmitters may mediate crosstalk between newly generated cells and the surrounding neuronal network (Masiulis et al, 2011). Under physiological conditions, DG neurogenesis is modulated by neural excitation (Deisseroth et al, 2004;Tozuka et al, 2005;Parent, 2007) and accumulating evidence indicates that neurotransmitters can influence the proliferation and differentiation of newborn cells (Ge et al, 2006;Jagasia et al, 2009;Jhaveri et al, 2010;Duveau et al, 2011;Song et al, 2012). GABA is the major inhibitory neurotransmitter in the adult brain acting via two main receptor types: ionotropic GABA A and G-protein coupled metabotropic GABA B receptors.…”

Neuropilin 2 Signaling Is Involved in Cell Positioning of Adult-born Neurons through Glycogen Synthase Kinase-3β (GSK3β)

“…These newly generated neurons form functional synapses with entorhinal cortical projections as well as with pre-existing neurons in the CA3 area (29,30). Several proteins have been shown to be involved in the positioning of the DG newborn neurons, including DISC-1, phospholipase C-␤1, GABA A receptor and NMDA receptor (3,6,10). However, it is still unclear how migration of newborn neurons in adult DG into different layers within GCL and into the molecular layer will affect their functions.…”

Effect of non-genomic actions of thyroid hormones on the anaesthetic effect of propofol

“…GABA is a natural inhibitory neurotransmitter, and the GABA receptor (GABAR) comprises GABA A R, GABA B R and GABA C R subclasses. Considering that GABA A R is a ligand-gated ion channel receptor, GABA can inhibit presynaptic neurotransmitter release and generate analgesia through a primary afferent depolarisation process by acting on GABA A R localised on primary afferent neurons (10,11). Approximately 19 known subunits (α1-6, β1-3, γ1-3, δ, ε, θ, π and ρ1-3) constitute the GABA A R (10,12), and all these subunits share an integral channel, which is permeable to Cl -ions.…”