Seizure activity within the hippocampal circuitry not only affects pre-existing structures, but also dramatically increases the number of newborn granule cells. A retroviral strategy was used to label dividing cells and their progeny in the adult dentate gyrus and to analyze the impact of epileptic activity on adult-generated cells labeled before or after seizures. We show that epileptic activity led to dramatic changes in the neuronal polarity, migration, and integration pattern of newborn granule cells, depending on the time of birth in relation to the epileptic insult. Aberrant neurons were stably integrated into the dentate circuitry, and the consequences on hippocampal neurogenesis were long lasting. The data presented characterized the consequences of seizure-associated plasticity on adult neurogenesis leading to long-term structural changes in the hippocampal circuitry that might represent a pivotal component of the epileptic disease process.
"ostnatal and adult hippocampal neurogenesis support hippocampal dependent learning and memory under physiological conditions (Dupret et al., 2007; Gould et al., 1999; Leuner et al., 2006; Shors et al., 2001; Winocur et al., 2006; Zhang et al., 2008). Furthermore, altered neurogenesis has been implicated in cognitive and mood impairment in temporal lobe epilepsy (Barkas et al., 2012; Kuruba et al., 2009), depression, and certain neurodegenerative diseases (Jessberger et al., 2007; Jin et al., 2004; Kempermann, 2002; Malberg et al., 2000; Parent et al., 1997; Rockenstein et al., 2007), suggesting that hippocampal neurogenesis may be an appropriate therapeutic target for these conditions. All these conditions have an important neuroinflammatory component to their pathogenesis, and the innate and adaptive immune systems are increasingly recognized as important control systems for hippocampal neurogenesis under both physiological and pathological conditions. "
[Show abstract][Hide abstract] ABSTRACT: Neurogenesis, the production of new neurons from neural stem/progenitor cells (NSPCs), occurs throughout adulthood in the dentate gyrus of the hippocampus, where it supports learning and memory. The innate and adaptive immune systems are increasingly recognized as important modulators of hippocampal neurogenesis under both physiological and pathological conditions. However, the mechanisms by which the immune system regulates hippocampal neurogenesis are incompletely understood. In particular, the role of microglia, the brains resident immune cell is complex, as they have been reported to both positively and negatively regulate neurogenesis. Interestingly, neuronal activity can also regulate the function of the immune system. Here, we show that depleting microglia from hippocampal cultures reduces NSPC survival and proliferation. Furthermore, addition of purified hippocampal microglia, or their conditioned media, is trophic and proliferative to NSPCs. VIP, a neuropeptide released by dentate gyrus interneurons, enhances the proliferative and pro-neurogenic effect of microglia via the VPAC1 receptor. This VIP-induced enhancement is mediated by IL-4 release, which directly targets NSPCs. This demonstrates a potential neuro-immuno-neurogenic pathway, disruption of which may have significant implications in conditions where combined cognitive impairments, interneuron loss, and immune system activation occurs, such as temporal lobe epilepsy and Alzheimer's disease. GLIA 2014
"Virus mediated birth-dating of granule cells 31-to 33-day-old male Wistar rats (95–135 g body weight) were injected with a CAG-GFP or CAG-RFP Moloney murine leukemia virus vector (Zhao et al., 2006; Jessberger et al., 2007) (0.8–1 µl) using stereotaxically targeted (5.7–5.8 mm posterior, ± 4.4–4.5 mm lateral, and 5.6–6 mm ventral from bregma), conventional Hamilton syringe under ketamine/xylazine/pipolphen anesthesia (83/17/7 mg/ body kg). Adult born granule cells were labeled along a broad longitudinal range (2–3 mm) of the hippocampi . "
[Show abstract][Hide abstract] ABSTRACT: Adult-born granule cells (ABGCs) are involved in certain forms of hippocampus-dependent learning and memory. It has been proposed that young but functionally integrated ABGCs (4-weeks-old) specifically contribute to pattern separation functions of the dentate gyrus due to their heightened excitability, whereas old ABGCs (>8 weeks old) lose these capabilities. Measuring multiple cellular and integrative characteristics of 3- 10-week-old individual ABGCs, we show that ABGCs consist of two functionally distinguishable populations showing highly distinct input integration properties (one group being highly sensitive to narrow input intensity ranges while the other group linearly reports input strength) that are largely independent of the cellular age and maturation stage, suggesting that 'classmate' cells (born during the same period) can contribute to the network with fundamentally different functions. Thus, ABGCs provide two temporally overlapping but functionally distinct neuronal cell populations, adding a novel level of complexity to our understanding of how life-long neurogenesis contributes to adult brain function.
"Normal granule neurons extend dendrites towards the molecular layer and project axons through the hilus. By contrast, dendrites from seizure-induced neurons grow ectopically towards the hippocampal hilus instead of the molecular layer (Jessberger et al., 2007; Hattiangady and Shetty, 2010). In addition, a significant decline in neurogenesis is observed in the aging brain (Jessberger and Gage, 2008; Villeda et al., 2011; Spalding et al., 2013). "
[Show abstract][Hide abstract] ABSTRACT: Granule neurons in the hippocampal dentate gyrus (DG) receive their primary inputs from the cortex and are known to be continuously generated throughout adult life. Ongoing integration of newborn neurons into the existing hippocampal neural circuitry provides enhanced neuroplasticity, which plays a crucial role in learning and memory; deficits in this process have been associated with cognitive decline under neuropathological conditions. In this Primer, we summarize the developmental principles that regulate the process of DG neurogenesis and discuss recent advances in harnessing these developmental cues to generate DG granule neurons from human pluripotent stem cells.
Development 06/2014; 141(12):2366-75. DOI:10.1242/dev.096776 · 6.46 Impact Factor
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