Early survival and delayed death of developmentally‐born dentate gyrus neurons

Abstract

The storage and persistence of memories depends on plasticity in the hippocampus. Adult neurogenesis produces new neurons that mature through critical periods for plasticity and cellular survival, which determine their contributions to learning and memory. However, most granule neurons are generated prior to adulthood; the maturational timecourse of these neurons is poorly understood compared to adult-born neurons but is essential to identify how the dentate gyrus (DG), as a whole, contributes to behavior. To characterize neurons born in the early postnatal period, we labeled DG neurons born on postnatal day 6 (P6) with BrdU and quantified maturation and survival across early (1 hr to 8 weeks old) and late (2-6 months old) cell ages. We find that the dynamics of developmentally-born neuron survival is essentially the opposite of neurons born in adulthood: P6-born neurons did not go through a period of cell death during their immature stages (from 1 to 8 weeks). In contrast, 17% of P6-born neurons died after reaching maturity, between 2 and 6 months of age. Delayed death was evident from the loss of BrdU cells as well as pyknotic BrdU caspase3 neurons within the superficial granule cell layer. Patterns of DCX, NeuN, and activity-dependent Fos expression indicate that developmentally-born neurons mature over several weeks and a sharp peak in zif268 expression at 2 weeks suggests that developmentally-born neurons mature faster than adult-born neurons (which peak at 3 weeks). Collectively, our findings are relevant for understanding how developmentally-born DG neurons contribute to memory and disorders throughout the lifespan. High levels of early survival and zif268 expression may promote learning, while also rendering neurons sensitive to insults at defined stages. Late neuronal death in young adulthood may result in the loss of hundreds of thousands of DG neurons, which could impact memory persistence and contribute to hippocampal/DG atrophy in disorders such as depression.

Dentate gyrus neurons that are born at the peak of development, but not before or after, die in adulthood

“…We therefore adjusted our criterion to include only cells that were unambiguously, strongly labeled with BrdU (≥50% of the nucleus stained). We found that ~150,000 granule neurons were born on P6, and there was a 15% loss of BrdU + cells between 2 and 6 months of age, replicating our previous findings (Cahill et al, 2017). Thus, this is likely a more accurate estimate of the true E19 value.…”

“…Since these numbers were comparable to our previous counts of P6-born cells (Cahill et al, 2017), and previous reports have indicated that prenatal neurogenesis is substantially lower than early postnatal neurogenesis (Bayer & Altman, 1974;Schlessinger et al, 1975), this criterion likely included many cells that were labeled by redivision and overestimated the true value. Since these numbers were comparable to our previous counts of P6-born cells (Cahill et al, 2017), and previous reports have indicated that prenatal neurogenesis is substantially lower than early postnatal neurogenesis (Bayer & Altman, 1974;Schlessinger et al, 1975), this criterion likely included many cells that were labeled by redivision and overestimated the true value.…”

“…Except where stated otherwise, methodological details are identical to those of our recent study of cell death in P6-born cells (Cahill et al, 2017). To label cells born prenatally (E19 group), rats were generated from timed pregnancies.…”

“…(b) DG granule neurons born on postnatal day 6. This population is known to undergo cell death in young adulthood (Cahill et al, 2017;Dayer et al, 2003). Postnatal day 6 is within the peak of DG development, so cells born at this time represent a large proportion of DG neurons (Schlessinger, Cowan, & Gottlieb, 1975).…”

Dopamine Modulates Homeostatic Excitatory Synaptic Plasticity of Immature Dentate Granule Cells in Entorhino-Hippocampal Slice Cultures

“…The dentate gyrus of the hippocampus is an attractive model to study homeostasis of immature neurons, since dentate granule cells (GCs) are born and differentiate postnatally, both in vivo (Altman and Das, 1965; van Praag et al, 2002; Toni et al, 2007; Kempermann et al, 2015; Nicola et al, 2015; Cahill et al, 2017; Radic et al, 2017a) and in vitro (Raineteau et al, 2004; Radic et al, 2017b). Previous work has demonstrated that immature GCs are capable of expressing Hebbian forms of synaptic plasticity, i.e., long-term potentiation (LTP) of excitatory synaptic strength (e.g., Schmidt-Hieber et al, 2004; Gonçalves et al, 2016).…”