High-Frequency Stimulation Induces Gradual Immediate Early Gene Expression in Maturing Adult-Generated Hippocampal Granule Cells

Abstract

Increasing evidence shows that adult neurogenesis of hippocampal granule cells is advantageous for learning and memory. We examined at which stage of structural maturation and age new granule cells can be activated by strong synaptic stimulation. High-frequency stimulation of the perforant pathway in urethane-anesthetized rats elicited expression of the immediate early genes c-fos, Arc, zif268 and pCREB133 in almost 100% of mature, calbindin-positive granule cells. In contrast, it failed to induce immediate early gene expression in immature doublecortin-positive granule cells. Furthermore, doublecortin-positive neurons did not react with c-fos or Arc expression to mild theta-burst stimulation or novel environment exposure. Endogenous expression of pCREB133 was increasingly present in young cells with more elaborated dendrites, revealing a close correlation to structural maturation. Labeling with bromodeoxyuridine revealed cell age dependence of stimulation-induced c-fos, Arc and zif268 expression, with only a few cells reacting at 21 days, but with up to 75% of cells activated at 35-77 days of cell age. Our results indicate an increasing synaptic integration of maturing granule cells, starting at 21 days of cell age, but suggest a lack of ability to respond to activation with synaptic potentiation on the transcriptional level as long as immature cells express doublecortin.

Activation of the CREB/c-Fos Pathway during Long-Term Synaptic Plasticity in the Cerebellum Granular Layer

“…These observations conform to a general scheme (West et al, 2002; Alberini, 2009), in which P-CREB primes a first wave of TFs activation (Sheng et al, 1990; Nedivi et al, 1993; Qian et al, 1993; Benito and Barco, 2015), which is followed by a second wave involving the IEGs, c-Fos (Morgan et al, 1987; Kaczmarek et al, 1988; Brindle and Montminy, 1992; Kaczmarek and Chaudhuri, 1997; Fleischmann et al, 2003; Flavell and Greenberg, 2008; Jungenitz et al, 2014; Benito and Barco, 2015). A simpler scheme involving new protein synthesis using pre-existing mRNA (Otani et al, 1989; Huang and Kandel, 2005; Barco et al, 2008) may not apply to the present case.…”

Time-lapse imaging reveals highly dynamic structural maturation of postnatally born dentate granule cells in organotypic entorhino-hippocampal slice cultures

“…Previous studies have reported a substantial decrease in neurogenesis in OTCs during the first week of cultivation4546. Since DCX expression can persist up to 3 weeks in individual GCs21224849, DCX-positive cells at DIV 28 may represent GCs that were generated at early time points but were still immature and continued to express DCX at the time of fixation. Alternatively, since neurogenesis does not cease completely in OTCs24254546, it could also be possible that a low number of GCs was generated at a later period.…”

“…Although the neurogenesis process seems to be progressing at a slower pace in the adult hippocampus, it shows many similarities to the embryonic development of GCs71819. While the time course of development is variable between individual GCs202122, in general, newly generated GCs in the postnatal brain need at least 5 weeks to mature and become fully integrated into the existing network1819. Current knowledge on the morphological development of newborn GCs is predominantly based on data obtained after the fixation of brains at different time points1819202223.…”

Brain Stimulation for Combating Alzheimer’s Disease

“…DBS probably reduces memory dysfunction by promoting the physiological conditions and patterns of extracellular field potentials necessary for long-term memory (56). Furthermore, there is evidence in rodents that fornix and perforant path stimulation increases hippocampal neurogenesis and long-term potentiation to facilitate memory storage (5, 57, 58). The nucleus basalis of Meynert (NBM) has several cholinergic projections, and it degenerates in AD, thus the NBM is a budding future target for DBS in AD (5, 59).…”