Enhanced Integration of Newborn Neurons after Neonatal Insults

Abstract

The production and integration of adult-generated neurons in the dentate gyrus is dramatically perturbed by a variety of pathological insults, including repetitive seizures and hypoxia/ischemia. Less is known about how insults affect early postnatal neurogenesis, during the developmental period when the majority of dentate neurons are produced. Here we tested how single episodes of hypoxia or chemically induced seizure activity in postnatal day 10 mice alter granule cell production and integration. Although neither insult was sufficient to alter the number of newborn neurons nor the population of proliferating cells, both treatments increased the dendritic complexity of newborn granule cells that were born around the time of the insult. Surprisingly, only the dendritic enhancement caused by hypoxia was associated with increased synaptic integration. These results suggest that alterations in dendritic integration can be dissociated from altered neural production and that integration appears to have a lower threshold for perturbation. Furthermore, newborn neurons in adult mice that experienced neonatal hypoxia had reduced dendritic length while having no alterations in number. Together these results suggest that single insults during the neonatal period can have both long- and short-term consequences for neuronal maturation.

In vivo effects of bumetanide at brain concentrations incompatible with NKCC1 inhibition on newborn DGC structure and spontaneous EEG seizures following hypoxia-induced neonatal seizures

“…It was believed that neural activity in the DG might affect the development of granule cell by both cell-autonomous and non-cell-autonomous mechanisms (Tozuka et al, 2005;Ge et al, 2006;Ma et al, 2009). In support of this idea, the enhanced dendritic structures in the newborn DGCs, one week after neonatal hypoxia, were associated with enhanced GABA-mediated synaptic inputs (Shapiro et al, 2005;Shapiro and Ribak, 2006;Walter et al, 2007;Pugh et al, 2011).…”

“…Recently, Pugh et al investigated the effects of neonatal seizures induced by hypoxia with P10 mice on the dendritic morphology of newborn DGCs and found that hypoxia-induced seizures increased the total dendritic length of newborn DGCs by 15% one week after seizure induction. However, the total dendritic length of newborn DGCs significantly decreased 2 month after seizure induction (Pugh et al, 2011). These results suggested that neonatal seizures induced by global hypoxia might distinctively impact short-and long-term consequences of dendritic development of newborn DGCs.…”

“…This finding suggested that proliferation of newborn DGCs was increased during seizure activity. However, Pugh et al subjected pups of mice to global hypoxia at P10 mice in order to induce seizures, and found that the number of newborn DGCs identified with POMC-GFP and proliferating cells identified with Ki67 at 1 week and 2 months after hypoxia-induced seizures were not affected (Pugh et al, 2011). Species-specific differences in development, or seizure response, time window observed, methods of cell labeling, could be the underlying reason for the discrepancy between the studies.…”

Klotho regulates postnatal neurogenesis and protects against age-related spatial memory loss

“…MicroBrightField, Williston, VA) (Pugh et al 2011). Cells with obvious truncation were excluded from analysis.…”

Using sex differences in the developing brain to identify nodes of influence for seizure susceptibility and epileptogenesis

“…One way in which this can occur is through altered neuron morphology and synaptogenesis, both of which are seen after neonatal seizures in the rat (Holmes et al, 2002; Pugh et al, 2011). As a fundamental developmental process, synaptogenesis is regulated in a sexually dimorphic manner under the influence of steroid hormones, as has been demonstrated in several areas of the brain in the neonatal rat.…”