New neurons continue to be born in the subgranular zone (SGZ) in the dentate gyrus (DG) of the adult mammalian hippocampus1–5. This process has been linked to learning and memory, stress and exercise, and is thought to be altered in neurological disease6–10. In humans, some studies suggest that hundreds of new neurons are added to the adult DG every day11, while other studies find many fewer putative new neurons12–14. Despite these discrepancies, it is generally believed that the adult human hippocampus continues to generate new neurons. Here we show that a defined population of progenitor cells does not coalesce in the SGZ during human fetal or postnatal development. We also find that proliferating progenitors and young neurons in the DG sharply decline in the first year of life and only a few isolated young neurons are observed by 7 and 13 years of age. In adult normal and epileptic patients(18–77 years; n=17 postmortem; n=12 epilepsy), young neurons were not detected in the DG. In the monkey (M. mulatta) hippocampus, a proliferative SGZ was present in early postnatal life, but diminished during juvenile development as neurogenesis declined. We conclude that recruitment of young neurons to the primate hippocampus declines rapidly during the first years of life, and that DG neurogenesis does not continue, or is extremely rare, in the adult human. The early decline in hippocampal neurogenesis raises questions about how the function of the dentate gyrus differs between humans and other species in which adult hippocampal neurogenesis is preserved.

SummaryMicroglia are well known to play a critical role in maintaining brain homeostasis. However, their role in epileptogenesis has yet to be determined. Here, we demonstrate that elevated mTOR signaling in mouse microglia leads to phenotypic changes, including an amoeboid-like morphology, increased proliferation, and robust phagocytosis activity, but without a significant induction of pro-inflammatory cytokines. We further provide evidence that these noninflammatory changes in microglia disrupt homeostasis of the CNS, leading to reduced synapse density, marked microglial infiltration into hippo-campal pyramidal layers, moderate neuronal degeneration, and massive proliferation of astrocytes. Moreover, the mice thus affected develop severe early-onset spontaneous recurrent seizures (SRSs). Therefore, we have revealed an epileptogenic mechanism that is independent of the microglial inflammatory response. Our data suggest that microglia could be an opportune target for epilepsy prevention.

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Activation of glial cells and the consequent release of cytokines, proteins, and other intercellular signaling molecules is a well‐recognized phenomenon in brain injury and neurodegenerative disease. We and others have previously described an inducible prostaglandin G/H synthase, known as PGHS‐2 or cyclooxygenase‐2, that is up‐regulated in many cell systems by cytokines and growth factors and down‐regulated by glucocorticoid hormones. In cultured mouse astrocytes we observed increased production of prostaglandin E2 (PGE2) after stimulation with either interleukin‐1β (IL‐1β) or the protein kinase C activator phorbol 12‐myristate 13‐acetate (TPA). This increase in PGE2 content was blocked by pretreatment with dexamethasone and correlated with increases in cyclooxygenase activity measured at 4 h. Northern blots revealed concomitant increases in PGHS‐2 mRNA levels that peaked at 2 h and were dependent on the dosage of IL‐1β. Dexamethasone inhibited this induction of PGHS‐2 mRNA by IL‐1β. TPA, basic fibroblast growth factor, and the proinflammatory factors tumor necrosis factor α and lipopolysaccharide, but not interleukin‐6, also stimulated PGHS‐2 mRNA expression. Relative to IL‐1β, the greater increases in PGE2 production and cyclooxygenase activity caused by TPA correlated with a greater induction of PGHS‐2 mRNA. Furthermore, NS‐398, a specific inhibitor of cyclooxygenase‐2, blocked >80% of the cyclooxygenase activity in TPA‐treated astrocytes. These findings indicate that increased expression of PGHS‐2 contributes to prostaglandin production in cultured astrocytes exposed to cytokines and other factors.

In paediatric epilepsy surgery patients with hemimegalencephaly (HME; n = 23), this study compared clinical, neuroimaging and pathologic features to discern potential mechanisms for suboptimal post-hemispherectomy developmental outcomes and structural pathogenesis. MRI measured affected and non-affected cerebral hemisphere volumes for HME and non-HME cases, including monozygotic twins where one sibling had HME. Staining against neuronal nuclei (NeuN) determined grey and white matter cell densities and sizes in HME and autopsy cases, including the non-affected side of a HME surgical/autopsy case. By MRI, the affected hemisphere was larger and the non-affected side smaller in HME compared with non-HME children. The affected HME side showed enlarged abnormal deep grey and white matter structures and/or T2-weighted hypointensity in the subcortical white matter in 75% of cases, suggestive of excessive pre-natal neurogenesis and heterotopias. Histopathological examination of the affected HME side revealed immature-appearing neurons in 70%, polymicrogyria (PMG) in 61% and balloon cells in 45% of cases. Compared with autopsy cases, in HME children NeuN cell densities on the affected side were increased in the molecular layer and upper cortex (+244 to +18%), decreased in lower cortical layers (-35%) and increased in the white matter (+139 to +149%). Deep grey matter MRI abnormalities and/or T2-weighted white matter hypointensity correlated with the presence of immature-appearing neurons and PMG on histopathology, decreased NeuN cell densities in lower cortical layers and a positive history of infantile spasms. Post-surgery seizure control was associated with decreased NeuN densities in the molecular layer. In young children with HME and epilepsy, these findings indicate that there are bilateral cerebral hemispheric abnormalities and contralateral hemimicrencephaly is a likely explanation for poorer post-surgery seizure control and cognitive outcomes. In addition, our findings support the hypothesis that HME pathogenesis probably involves somatic mutations that affect each developing cerebral hemisphere differently with more neurons than expected on the HME side.