Long-Range GABAergic Inputs Regulate Neural Stem Cell Quiescence and Control Adult Hippocampal Neurogenesis

Abstract

Summary The quiescence of adult neural stem cells (NSCs) is regulated by local parvalbumin (PV) interneurons within the dentate gyrus (DG). Little is known about how local PV interneurons communicate with distal brain regions to regulate NSCs and hippocampal neurogenesis. Here we identify GABAergic projection neurons from the medial septum (MS) as the major afferents to dentate PV interneurons. Surprisingly, dentate PV interneurons are depolarized by GABA signaling, which is in sharp contrast to most mature neurons hyperpolarized by GABA. Functionally, these long-range GABAergic inputs are necessary and sufficient to maintain adult NSC quiescence, and ablating them leads to NSC activation and subsequent depletion of the NSC pool. Taken together, these findings delineate a GABAergic network involving long-range GABAergic projection neurons and local PV interneurons that couples dynamic brain activity to the neurogenic niche in controlling NSC quiescence and hippocampal neurogenesis.

The α7 nicotinic acetylcholine receptors regulate hippocampal adult-neurogenesis in a sexually dimorphic fashion

“…In addition, a small subset of somatostatin + interneurons with cell bodies in the hilus and dendrites that project to the molecular layer inhibit neurons locally and in the medial septum and diagonal band of Broca (MS/DBB) (Yuan et al 2017) which could be impacting adult neurogenesis. Interestingly, parvalbumin + interneurons receive input from the MS/DBB (Bao et al 2017), and loss of this input causes activation of NSCs with a decline in NSC pools. While the largest input onto these interneurons appears to be GABAergic, the MS/DBB also have cholinergic neurons both modulating GABAergic locally and projection neurons in intraseptal circuitry (Damborsky et al 2017), as well as directly activating interneurons in the hippocampus (Dannenberg et al 2015).…”

“…Pathogenic conditions that impact adult neurogenesis (Hollands et al 2016; Jessberger and Parent 2015; Kang et al 2016) are also linked to the disruption in cholinergic innervation. The dentate gyrus receives input from the basal forebrain through GABAergic and cholinergic projection neurons (Bao et al 2017; Cooper-Kuhn et al 2004), and the infusion of fibroblasts releasing acetylcholine (ACh) into the hippocampus reverses cognitive decline (Dickinson-Anson et al 2003). Anti-cholinesterases, which inhibit the breakdown of acetylcholine, increase adult neurogenesis (Kotani et al 2006) and promote survival of immature neurons through the α7 subtype of nicotinic ACh receptors (nAChRs) (Kita et al 2014).…”

Id4 eliminates the pro-activation factor Ascl1 to maintain quiescence of adult hippocampal stem cells

“…Extensive work has led to the identification of extracellular signals present in the SEZ and DG niches that regulate quiescent and active states (Choe et al, 2015; Silva-Vargas et al, 2013). Notch, BMP4 and the neurotransmitter GABA have been shown to maintain stem cell quiescence while Wnt and Shh are thought to promote stem cell activity (Bao et al, 2017; Choe et al, 2015; Engler et al, 2018; Imayoshi et al, 2010; Lie et al, 2005; Mira et al, 2010; Petrova et al, 2013; Qu et al, 2010; Song et al, 2012). However, little is known of the cell intrinsic machinery that NSCs employ to adjust their activity to the different signals received from the niche.…”

Evidence of progenitor cell lineage rerouting in the adult mouse hippocampus

“…In contrast, increased network activity in the contralateral KA-injected side and both hippocampi of PL-injected animals could be coupled to an enhanced GABA activity, favoring neuronal differentiation and survival (Bao et al, 2017;Jagasia et al, 2009). For example, hilar BDNF infusion for two weeks in naïve animals boosts neuronal excitability and is sufficient to increase neurogenesis (Scharfman et al, 2005).…”