GABAergic Excitation Promotes Neuronal Differentiation in Adult Hippocampal Progenitor Cells

Abstract

Hippocampal activity influences neurogenesis in the adult dentate gyrus; however, little is known about the involvement of the hippocampal circuitry in this process. In the subgranular zone of the adult dentate gyrus, neurogenesis involves a series of differentiation steps from radial glia-like stem/progenitor (type-1) cells, to transiently amplifying neuronal progenitor (type-2) cells, to postmitotic neurons. In this study, we conducted GFP-targeted recordings of progenitor cells in fresh hippocampal slices from nestin-GFP mice and found that neuronal progenitor (type-2) cells receive active direct neural inputs from the hippocampal circuitry. This input was GABAergic but not glutamatergic. The GABAergic inputs depolarized type-2 cells because of their elevated [Cl(-)](i). This excitation initiated an increase of [Ca(2+)](i) and the expression of NeuroD. A BrdU-pulse labeling study with GABA(A)-R agonists demonstrated the promotion of neuronal differentiation via this GABAergic excitation. Thus, it appears that GABAergic inputs to hippocampal progenitor cells promote activity-dependent neuronal differentiation.

Molecular layer perforant path-associated cells contribute to feed-forward inhibition in the adult dentate gyrus

“…At early stages, GABA depolarizes neurons because of high concentrations of intracellular Cl − (30). Although glutamatergic inputs from entorhinal cortex to newborn neurons are not detected at very early stages (31,32), cortical afferent activity may still be able to depolarize new neurons through the feed-forward mechanism mediated by interneurons such as MOPP cells. Such a mechanism might allow external cortical inputs to regulate neurogenesis, including neural stem cell proliferation, survival, and differentiation as well as the subsequent integration of the new neurons into the existing neural circuit.…”

Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression

“…59 Finally, there is evidence that in adult mouse hippocampal slices, GABAergic synaptic inputs depolarize proliferating progenitor cells, contributing to their later differentiation and functional incorporation into the dentate gyrus. 60,61 Thus, improper regulation of GAD 67 , either during development or adulthood, has the potential to produce a variety of phenotypic results, some of which may increase the risk of schizophrenia.…”

Neural stem cells: mechanisms and modeling

“…Functionally, the GABA-induced excitatory transmission acts as a developmental compensation for the largely absent glutamatergic transmission, especially AMPAR-mediated responses, in young neurons. GABAR activation promotes neuronal differentiation in the SGZ and neuroblast migration in the SVZ (Tozuka et al, 2005;Ge et al, 2006;Mejia-Gervacio et al, 2011). On the other hand, in the SVZ, the GABAergic transmission can delay the proliferation of NSCs (Liu et al, 2005).…”