Endogenous but not sensory-driven activity controls migration, morphogenesis and survival of adult-born neurons in the mouse olfactory bulb

Abstract

The integration of adult-born neurons in the existent neural circuitry is known to be activity-dependent. To decipher the underlying mechanisms, we genetically manipulated excitability of adult-born cells (via cell-specific overexpression of either Kv1.2 or Kir2.1 K+ channels). Longitudinal in vivo Ca2+ imaging and transcriptome analyses revealed that endogenous but not sensory-driven activity governs migration, morphogenesis, survival, and functional integration of adult-born juxtaglomerular neurons in the mouse olfactory bulb. The proper development of these cells required fluctuations of cytosolic Ca2+ levels, phosphorylation of CREB, and pCREB-mediated gene expression. Attenuating Ca2+ fluctuations via K+ channel overexpression strongly downregulated genes involved in neuronal migration, differentiation, and morphogenesis and upregulated the apoptosis-related genes, thus locking adult-born cells in the vulnerable and immature state. Together, the data identify signaling pathways connecting the endogenous intermittent neuronal activity/Ca2+ fluctuations as well as proper Kv1.2/Kir2.1 K+ channel function to migration, maturation, and survival of adult-born neurons.

Genetically modified peripheral neurons transplant aided activity maintenance and secretome modulation: a novel strategy for spinal cord injury treatment

“…This result agrees with previous reports of increased migratory and engraftment capacity in developing neurons in the olfactory system after NaChBac expression [228]. Since endogenous Ca 2+ and neuronal activity play essential roles in neuronal migration [289], the endogenous activity of DRG neurons may be associated with this increased migrating capacity.…”

Impairment of brain function in a mouse model of Alzheimer’s disease during the pre-depositing phase: the role of α7 nicotinic acetylcholine receptors

“…The underlying mechanisms are likely synaptic, including the α7-mediated activation of the Ca 2+ -dependent Ca 2+ /calmodilin-CaMKII-CREB signaling pathway, with the subsequent upregulation of the pCREB-dependent genes (e.g. c-Fos, NMDA receptors, p-TrkB, BDNF) [61], critically important for learning and memory [36, 59]. When starting, as in the current study, the α7 receptor agonist-mediated treatment during the early disease stage, additional advantages are obtained.…”

Enhanced endogenous activity predicts elimination of adult-born neurons in the mouse olfactory bulb

“…4d, P = 0.97, Mann-Whitney test). To test whether longitudinal imaging might enhance the elimination of abJGNs, we compared the fractions of surviving cells in our RGB and Twitch-2B group to a dataset from our laboratory (Li et al, 2021), in which Twitch-2B + abJGNs were imaged only at 2 time points: either at DPI 14 and 25 or DPI 25 and 45. We did not detect any significant difference both at DPI 14/25 (2-time-points group: 62.50 ± 23.41%, n = 5 mice; RGB group: 61.18 ± 24.24%, n = 12 mice; P = 0.65, Mann-Whitney test) and DPI 25/45 (2-time-points group: 80.00 ± 20.76%, n = 5 mice; RGB group: 96.29 ± 7.33%, n = 12 mice; Twitch-2B group: 94.74 ± 4.48%, n = 11 mice; P = 0.07, Kruskal-Wallis test), suggesting that our longitudinal imaging protocol did not promote the elimination of abJGNs.…”

“…It was suggested that fluctuations of [Ca 2+ ]i rather than mere Ca 2+ influx are needed to drive the phosphorylation of nuclear cAMP-response-element-binding protein (CREB; Li et al, , 2009, a known key mediator of the development and survival of ABCs (Giachino et al, 2005;Jagasia et al, 2009;Li et al, , 2021. To determine whether abJGNs were eliminated because their [Ca 2+ ]i was unable to fluctuate, we analyzed the fluctuations of [Ca 2+ ]i both in eliminated and surviving abJGNs (see Methods).…”

“…'stop-and-go'-like) radial migration (Liang et al, 2016). Whereas GCs stop at the end of the radial migration phase, abJGNs speed up and, after arrival into the glomerular layer, switch from the radial to the long-distance, uni-or multi-directional lateral migration, lasting till the end of the pre-integration phase (~3-4 weeks after ABCs' birth) (Li et al, 2021;Liang et al, 2016).…”