Cell Reports
Preview Newborn Neurons in the Aged Hippocampus—Scarce and Slow but Highly Plastic Ruth Beckervordersandforth1,* 1Institute of Biochemistry, Emil Fischer Center, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany *Correspondence:
[email protected] https://doi.org/10.1016/j.celrep.2017.10.049
In this issue of Cell Reports, Trinchero et al. (2017) demonstrate that newborn neurons in the aged hippocampus are delayed in development but are highly susceptible to stimuli improving neuronal activity. This plasticity is mediated cell-intrinsically by neurotrophin signaling. The adult mammalian brain is a highly dynamic structure capable of responding to physiological and pathological stimuli. A key contribution to adult brain plasticity is the continuous generation of new neurons (neurogenesis) and their integration into pre-existing circuits. Adult neurogenesis is restricted to specific areas of the brain (Bond et al., 2015), including the hippocampus, a structure involved in higher cognitive functions such as spatial learning and episodic memory as well as mood regulation. Adult neurogenesis is of strong clinical interest, as its dysregulation is a significant contributor to neuropsychiatric symptoms in aging and neurodegenerative diseases (Winner et al., 2011); in the aged hippocampus, generation, differentiation, and survival of newborn neurons are reduced (Kuhn et al., 1996; van Praag et al., 2005). Neuronal circuit dynamics are impaired due to altered synaptic transmission and loss of synapses, leading to reduced long-term potentiation (Burke and Barnes, 2010). Consequently, there is currently intense interest in the mechanisms of impaired neurogenesis and the development of strategies to enhance neurogenesis during aging. In this issue of Cell Reports, Trinchero et al. (2017) inquire how newborn neurons in the aged brain establish synaptic connections to integrate into neural circuits. The authors analyzed how pro-neurogenic stimuli boost this integration and examined the potential mechanisms underlying plasticity in the aged hippocampus. Neuronal development involves a complex sequence of differentiation and maturation steps that are reflected in the
neuron’s morphology (Figure 1A). To compare neuronal development of hippocampal granule cells in young (2-monthold) and middle-aged (5- and 8-monthold) mice, the authors labeled newborn neurons using retroviral vectors expressing GFP and conducted a thorough morphological analysis at various times after injection. This revealed an ageinduced developmental delay, as granule neurons born in 8-month-old mice took much longer to properly develop dendrites (42 days) and spines (28 days) than neurons born in young mice (21 days; Figure 1B). Notably, once matured, newborn neurons displayed similar dendritic features and spine density values irrespective of the age of the mouse. To probe plasticity of newborn neurons in the aged brain, Trinchero et al. (2017) exposed middle-aged mice to pro-neurogenic conditions such as running wheels and enriched environment. Voluntary physical activity is the most potent known stimulus to enhance adult neurogenesis in the hippocampus, where it induces neural precursor cell proliferation (Overall et al., 2016). Environmental enhancement, by contrast, improves survival and integration of newborn neurons (Alvarez et al., 2016). Both pro-neurogenic conditions significantly accelerated neuronal development in middle-aged mice; after 21 days, newborn neurons displayed similar structural features as in young mice. Importantly, running facilitated the integration of newborn neurons into local circuits. Electrophysiological recordings of 21-day-old granule neurons in slice
cultures from running middle-aged animals showed repetitive firing and spontaneous glutamatergic postsynaptic currents, while newborn neurons from sedentary mice of the same age revealed an incipient phenotype lacking functional glutamatergic input. These results demonstrate that neurons born in 8-month-old mice—despite being scarce and slow—are still highly sensitive to hippocampal stimulation induced by running or experience. Which mechanisms explain this running-induced neuronal integration in the aged hippocampus? Given its wellknown role in dendritic development of adult-born neurons and its correlation with neuronal activity (Park and Poo, 2013), the authors identified neurotrophin signaling as a good candidate. In the aging hippocampus, delayed development of newborn neurons was paralleled by decreased activity of the granule cell layer and reduced expression of brain-derived neurotrophic factor (BDNF). Voluntary exercise increased activity of the granule cell layer as well as BNDF levels in middle-aged mice. These results led to the hypothesis that neuronal activity combined with cell-intrinsic effects of neurotrophin signaling underlie beneficial effects of running in middle-aged mice. To see how chronic neuronal activity affects dendritic growth of newborn granule neurons in middle-aged mice, Trinchero et al. (2017) used a chemogenetic approach, retrovirally expressing the synthetic G protein-coupled receptor hM3Dq in newborn neurons. Binding of the synthetic ligand clozapine-N-oxid to
Cell Reports 21, October 31, 2017 ª 2017 The Author(s). 1127 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
A
hippocampal neurogenic lineage
2 month-old mice
aging
8 month-old mice
neurotrophin
neurotrophin
intrinsic neural stem cell progenitor cell neuroblast immature neurons
extrinsic
21 days
neuronal activity
B 2 months
8 months sedentary
voluntary exercise
enriched environment
neuronal depolarisation (hM3Dq+ CNO)
neurotrophin signalling shLrig
neurotrophin signalling oeLrig
Figure 1. Development of Newborn Neurons in the Aged Hippocampus under Conditions of Enhanced and Impaired Plasticity (A) Schematic illustrating the hippocampal stem cell lineage and summarizing the findings of Trinchero et al. (2017). 21-day-old newborn neurons in 2-month-old mice (red boxes) showed a pronounced morphology with long and branched dendrites and spines. In 8-month-old brains, 21-day-old neurons (gray boxes) displayed short dendrites, few branches, and no spines. Neuronal activity and enhanced neurotrophin signaling can significantly accelerate neuronal development in the aged hippocampus. (B) Morphological reconstructions of 21-day-old retrovirally labeled newborn neurons under different experimental conditions, as shown in Trinchero et al. (2017). Scale bar, 20 mm.
hM3Dq induced neuronal depolarization, leading to accelerated dendritic growth of new neurons in 8-month-old mice comparable to that induced by running. Next, the authors investigated the cellintrinsic effects of neurotrophin signaling by knocking down Lrig1, an endogenous negative regulator of tyrosine kinase receptors (including neurotrophin receptors) in newborn granule neurons of middle-aged mice. Three weeks after Lrig1 knockdown, the same positive effect on dendritic growth was observed as that induced by running. Moreover, running combined with Lrig1 knockdown in 8-month-old animals was strong enough to hasten dendritic development in 14-day-old newborn neurons that were
1128 Cell Reports 21, October 31, 2017
unaffected by running or Lrig1 knockdown alone. Conversely, overexpression of Lrig1 in newly generated granule neurons of middle-aged running mice abolished dendritic growth. Thus, inhibition of neurotrophin signaling prevented enhanced neuronal growth induced by activity. In summary, Trinchero et al. (2017) show that newborn granule neurons in the aged brain develop slowly but retain significant plasticity, allowing them to integrate into local circuits in an activitydependent manner. A key finding is that the cell-intrinsic mediator of facilitated integration of newborn neurons is neurotrophin signaling. It will be most interesting to investigate whether neurotrophin signaling is altered upon neurodegenera-
tion and to what extent it can ameliorate neurogenesis-dependent cognitive deficits. There are still many questions to be answered: why do neuronal activity and BNDF levels decrease with age? Is BDNF part of a bigger network? This is particularly interesting in regard to VEGF (vascular endothelial growth factor), which also signals via tyrosine kinase receptors and mediates the effect of environmental stimulation on neurogenesis and cognition (Cao et al., 2004). Trinchero et al. (2017) have paved the way for future investigations on the effect of neuronal activity and neurotrophin signaling on hippocampal plasticity in healthy as well as in aging and neurodegenerative conditions. REFERENCES Alvarez, D.D., Giacomini, D., Yang, S.M., Trin€ttner, K.A., Beltrachero, M.F., Temprana, S.G., Bu mone, N., and Schinder, A.F. (2016). Science 354, 459–465. Bond, A.M., Ming, G.L., and Song, H. (2015). Cell Stem Cell 17, 385–395. Burke, S.N., and Barnes, C.A. (2010). Trends Neurosci. 33, 153–161. Cao, L., Jiao, X., Zuzga, D.S., Liu, Y., Fong, D.M., Young, D., and During, M.J. (2004). Nat. Genet. 36, 827–835. Kuhn, H.G., Dickinson-Anson, H., and Gage, F.H. (1996). J. Neurosci. 16, 2027–2033. Overall, R.W., Walker, T.L., Fischer, T.J., Brandt, M.D., and Kempermann, G. (2016). Front. Neurosci. 10, 362. Park, H., and Poo, M.M. (2013). Nat. Rev. Neurosci. 14, 7–23. Trinchero, M.F., Buttner, K.A., Cuevas, J.N.S., Temprana, S.G., Fontanet, P.A., Monzo´n-Salinas, M.C., Ledda, F., Paratcha, G., and Schinder, A.F. (2017). Cell Rep. 21, this issue, 1129–1139. van Praag, H., Shubert, T., Zhao, C., and Gage, F.H. (2005). J. Neurosci. 25, 8680–8685. Winner, B., Kohl, Z., and Gage, F.H. (2011). Eur. J. Neurosci. 33, 1139–1151.
