Arcuate Nucleus Neurons Regulate Ventral Subregion Ventricular-Subventricular Zone Neural Stem Progenitor Cell Differentiation Through Endocannabinoid Signaling

Abstract

Neural stem and progenitor cells in the ventricular-subventricular zone (V-SVZ) have been a long sought-after source of neurogenic potency. Although activation signals for NSPCs are well-described, difficulties arise in harnessing these NSPCS as isolating differentiation-specific signals remain elusive in vivo. Here, we report that monoacylglycerol lipase (Mgll), a homeostatic enzyme that attenuates synaptic endocannabinoid responses, is a physiological gatekeeper for NSPC differentiation. Remarkably, Mgll expression is non-cell autonomous, originating in axons from neurons innervating the V-SVZ. Furthermore, pathological conditions show early spatiotemporally-distinct overexpression of Mgll in the hypothalamic arcuate nucleus (ARC) of 3xTg Alzheimer’s disease mice (3xTg-AD). ARC Mgll overexpression is coupled to inhibition of differentiation and neurogenesis in the ventral V-SVZ subregion, culminating in olfactory behavioral deficits. Mechanistically, this spatiotemporal Mgll overexpression and subsequent ventral V-SVZ differentiation deficits originate from defective ARC-specific aPKC-CBP signaling. Conversely, spatial transcriptomics shows Mgll deletion in ARC POMC+ neurons increases ventral V-SVZ-specific expression of pro-differentiation transcription factors Nf1x and Nf1b, driving neurogenic and gliogenic lineage commitment. Finally, deleting Mgll in the ARC from mice with dysregulated aPKC-CBP signaling rescues ventral V-SVZ-derived neurogenesis deficits through Nf1x expression. Our study implicates a neuronal homeostatic mechanism in regulating V-SVZ NSPC differentiation and demonstrates that this mechanism is spatiotemporally dysregulated under pathological conditions. These findings show that interacting with neuronally-derived Mgll is a promising strategy to precisely restore neurogenic potency.