Cell-autonomous inactivation of the reelin pathway impairs adult neurogenesis in the hippocampus.

Adult hippocampal neurogenesis is thought to be essential for learning and memory, and has been implicated in the pathogenesis of several disorders. Although recent studies have identified key factors regulating neuroprogenitor proliferation in the adult hippocampus, the mechanisms that control the migration and integration of adult-born neurons into circuits are largely unknown. Reelin is an extracellular matrix protein that is vital for neuronal development. Activation of the Reelin cascade leads to phosphorylation of Disabled-1, an adaptor protein required for Reelin signaling. Here we used transgenic mouse and retroviral reporters along with Reelin signaling gain-of-function and loss-of-function studies to show that the Reelin pathway regulates migration and dendritic development of adult-generated hippocampal neurons. Whereas overexpression of Reelin accelerated dendritic maturation, inactivation of the Reelin signaling pathway specifically in adult neuroprogenitor cells resulted in aberrant migration, decreased dendrite development, formation of ectopic dendrites in the hilus, and the establishment of aberrant circuits. Our findings support a cell-autonomous and critical role for the Reelin pathway in regulating dendritic development and the integration of adult-generated granule cells and point to this pathway as a key regulator of adult neurogenesis. Moreover, our data reveal a novel role of the Reelin cascade in adult brain function with potential implications for the pathogenesis of several neurological and psychiatric disorders.

The developmental stage of dentate granule cells dictates their contribution to seizure-induced plasticity.

Dentate granule cell (DGC) neurogenesis persists throughout life in the hippocampal dentate gyrus. In rodent temporal lobe epilepsy models, status epilepticus (SE) stimulates neurogenesis, but many newborn DGCs integrate aberrantly and are hyperexcitable, whereas others may integrate normally and restore inhibition. The overall influence of altered neurogenesis on epileptogenesis is therefore unclear. To better understand the role DGC neurogenesis plays in seizure-induced plasticity, we injected retroviral (RV) reporters to label dividing DGC progenitors at specific times before or after SE, or used x-irradiation to suppress neurogenesis. RV injections 7 weeks before SE to mark DGCs that had matured by the time of SE labeled cells with normal placement and morphology 4 weeks after SE. RV injections 2 or 4 weeks before seizure induction to label cells still developing during SE revealed normally located DGCs exhibiting hilar basal dendrites and mossy fiber sprouting (MFS) when observed 4 weeks after SE. Cells labeled by injecting RV after SE displayed hilar basal dendrites and ectopic migration, but not sprouting, at 28 d after SE; when examined 10 weeks after SE, however, these cells showed robust MFS. Eliminating cohorts of newborn DGCs by focal brain irradiation at specific times before or after SE decreased MFS or hilar ectopic DGCs, supporting the RV labeling results. These findings indicate that developing DGCs exhibit maturation-dependent vulnerability to SE, indicating that abnormal DGC plasticity derives exclusively from aberrantly developing DGCs. Treatments that restore normal DGC development after epileptogenic insults may therefore ameliorate epileptogenic network dysfunction and associated morbidities.

Behavioral effects of toluene in rats selectively bred for infantile vocalization rate.

Glue sniffing is epidemic among children living in poverty in Latin America. Previous research has shown that abused inhalants such as toluene share pharmacological properties with anxiolytic drugs, and that personality factors such as degree of anxiety have been proposed to modulate the effects of these drugs. To study this interaction in an animal model, rats selectively bred for high (High) or low (Low) rates of distress calls after maternal separation (ultrasonic vocalizations, USVs) were used to investigate toluene's acute and long-term effects on two measures of anxiety behavior. At ten days of age, neonatal subjects were administered toluene (1 g/kg i.p.) and USVs were recorded. The subjects were retested as juveniles on an elevated plus maze to examine sequela of earlier toluene exposure. Acute toluene administration reduced USVs relative to control groups in neonates of both lines, indicating anxiolysis. As expected, Lows had reduced USVs relative to Highs. At 28 days of age, Highs spent more time in the open arms of the elevated plus maze than Lows. However, prior neonatal toluene exposure blocked this reversal of behavioral phenotype. This suggests that early toluene exposure compromised a compensatory process occurring during this developmental period, which may have been maternally mediated. These results have implications for the effects of early drug exposure on plasticity in the developing nervous system.

Late-onset cystoid macular edema as a presenting symptom of anca-negative pauciimmune crescentic glomerulonephritis.

PURPOSE: The purpose of this study was to report the appearance of late-onset cystoid macular edema (CME) as an initial manifestation of antineutrophil cytoplasmic antibody-negative pauciimmune glomerulonephritis. METHODS: Optical coherence tomography was obtained on a female patient after presentation of CME after cataract surgery in the right eye. Follow-up optical coherence tomographies were obtained after resolution of symptoms and on development and resolution of CME in the fellow eye. RESULTS: The patient developed unilateral CME 6 months after uncomplicated cataract surgery and after a seizure was diagnosed with antineutrophil cytoplasmic antibody-negative pauciimmune glomerulonephritis. The CME resolved within 2 months of initiating topical nonsteroidal antiinflammatory drug and steroid treatment. Several months later, after undergoing uncomplicated cataract surgery in the fellow eye, the patient developed CME 4 weeks after surgery despite topical nonsteroidal antiinflammatory drug and steroid prophylaxis. The CME quickly resolved with topical treatment, and there has been no recurrent CME in either eye. Review of the literature shows a potential shared mechanism of CME and antineutrophil cytoplasmic antibody-negative pauciimmune glomerulonephritis. CONCLUSION: These findings demonstrate a potential association between CME and antineutrophil cytoplasmic antibody-negative pauciimmune glomerulonephritis. Patients with this form of glomerulonephritis may benefit from pre- and postoperative topical antiinflammatory prophylaxis.