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GABAergic interneurons tend to diversify into similar classes across telencephalic regions. However, it remains unclear whether the electrophysiological and molecular properties commonly used to define these classes are discriminant in the hilus of the dentate gyrus. Here, using patch-clamp combined with single cell RT-PCR, we compare the relevance of commonly used electrophysiological and molecular features for the clustering of GABAergic interneurons sampled from the mouse hilus and primary sensory cortex. While unsupervised clustering groups cortical interneurons into well-established classes, it fails to provide a convincing partition of hilar interneurons. Statistical analysis based on resampling indicates that hilar and cortical GABAergic interneurons share limited homology. While our results do not invalidate the use of classical molecular marker in the hilus, they indicate that classes of hilar interneurons defined by the expression of molecular markers do not exhibit strongly discriminating electrophysiological properties., Competing Interests: The authors have declared that no competing interests exist.

The neural cell adhesion molecule (NCAM) is known to play a role in developmental and structural processes but also in synaptic plasticity and memory of the adult animal. Recently, FGL, a NCAM mimetic peptide that binds to the Fibroblast Growth Factor Receptor 1 (FGFR-1), has been shown to have a beneficial impact on normal memory functioning, as well as to rescue some pathological cognitive impairments. Whether its facilitating impact may be mediated through promoting neuronal plasticity is not known. The present study was therefore designed to test whether FGL modulates the induction and maintenance of synaptic plasticity in the dentate gyrus (DG) in vivo. For this, we first assessed the effect of the FGL peptide on synaptic functions at perforant path-dentate gyrus synapses in the anesthetized rat. FGL, or its control inactive peptide, was injected locally 60 min before applying high-frequency stimulation (HFS) to the medial perforant path. The results suggest that although FGL did not alter basal synaptic transmission, it facilitated both the induction and maintenance of LTP. Interestingly, FGL also modified the heterosynaptic plasticity observed at the neighboring lateral perforant path synapses. The second series of experiments, using FGL intracerebroventricular infusion in the awake animal, confirmed its facilitating effect on LTP for up to 24 h. Our data also suggest that FGL could alter neurogenesis associated with LTP. In sum, these results show for the first time that enhancing NCAM functions by mimicking its heterophilic interaction with FGFR facilitates hippocampal synaptic plasticity in the awake, freely moving animal.

Activity-dependent synaptic plasticity and neurogenesis are two forms of brain plasticity that can participate in functional remodeling of neural networks during the formation of memories. We examined whether long-term potentiation (LTP) of excitatory synaptic transmission, a well characterized form of synaptic plasticity believed to play a critical role in memory formation, can regulate the rate of neurogenesis in the adult rat dentate gyrus in vivo. We first show that induction of LTP at medial perforant path-granule cell synapses stimulates the proliferation of progenitor cells in the dentate gyrus with a consequential long-term persistence of a larger population of surviving newborn cells. Using protocols to examine the effect of LTP on survival, we next show that LTP induction promotes survival of 1- to 2-week-old dentate granule cells. In no case did LTP appear to affect neuronal differentiation. Finally, we show that LTP induces expression of the plasticity-related transcription factor Zif268 in a substantial fraction of 2-week-old but not 1-week-old neurons, suggesting the prosurvival effect of LTP can be observed in the absence of LTP-mediated Zif268 induction in newborn cells. Our results indicate that electrically induced LTP in the dentate gyrus in vivo provides a cellular/molecular environment that favors both proliferation and survival of adult-generated neurons.

Although thousands of new neurons are continuously produced in the dentate gyrus of rodents each day, the function of these newborn cells remains unclear. An increasing number of reports have provided correlational evidence that adult hippocampal neurogenesis is involved in learning and memory. Exposure of animals to an enriched environment leads to improvement of performance in several learning tasks and enhances neurogenesis specifically in the hippocampus. These data raise the question of whether new neurons participate in memory improvement induced by enrichment. To address this issue, we have examined whether the increase in the number of surviving adult-generated cells following environmental enrichment contributes to improved memory function. To this end, neurogenesis was substantially reduced throughout the environmental enrichment period using the antimitotic agent methylazoxymethanol acetate (MAM). Recognition memory performance of MAM-treated enriched rats was evaluated in a novel object recognition task and compared with that of naive and nontreated enriched rats. Injections of 5-bromo-2'-deoxyuridine were used to label dividing cells, together with double immunofluorescent labelling using glial or neuronal cell-specific markers. We found that enrichment led to improved long-term recognition memory and increased hippocampal neurogenesis, and that MAM treatment during environmental enrichment completely prevented both the increase in neurogenesis and enrichment-induced long-term memory improvement. These results establish that newborn cells in the dentate gyrus contribute to the expression of the promnesic effects of behavioural enrichment, and they provide further support for the idea that adult-generated neurons participate in modulating memory function.

Alzheimer's disease (AD) is characterized by severe neuronal loss in several brain regions important for learning and memory. Of the structures affected by AD, the hippocampus is unique in continuing to produce new neurons throughout life. Mounting evidence indicates that hippocampal neurogenesis contributes to the processing and storage of new information and that deficits in the production of new neurons may impair learning and memory. Here, we examine whether the overproduction of amyloid-β(Aβ) peptide in a mouse model for AD might be detrimental to newborn neurons in the hippocampus. We used transgenic mice overexpressing familial AD variants of amyloid precursor protein (APP) and/or presenilin-1 to test how the level (moderate or high) and the aggregation state (soluble or deposited) of Aβ impacts the proliferation and survival of new hippocampal neurons. Although proliferation and short-term survival of neural progenitors in the hippocampus was unaffected by APP/Aβ overproduction, survival of newborn cells 4 weeks later was dramatically diminished in transgenic mice with Alzheimer's-type amyloid pathology. Phenotypic analysis of the surviving population revealed a specific reduction in newborn neurons. Our data indicate that overproduction of Aβ and the consequent appearance of amyloid plaques cause an overall reduction in the number of adult-generated hippocampal neurons. Diminished capacity for hippocampal neuron replacement may contribute to the cognitive decline observed in these mice. [ABSTRACT FROM AUTHOR]

In recent decades, neurogenesis in the adult brain has been well demonstrated in a number of animal species, including humans. Interestingly, work with rodents has shown that adult neurogenesis in the dentate gyrus (DG) of the hippocampus is vital for some cognitive aspects, as increasing neurogenesis improves memory, while its disruption triggers the opposite effect. Adult neurogenesis declines with age and has been suggested to play a role in impaired progressive learning and memory loss seen in Alzheimer's disease (AD). Therefore, therapeutic strategies designed to boost adult hippocampal neurogenesis may be beneficial for the treatment of AD. The precursor forms of neurotrophins, such as pro-NGF, display remarkable increase during AD in the hippocampus and entorhinal cortex. In contrast to mature NGF, pro-NGF exerts adverse functions in survival, proliferation, and differentiation. Hence, we hypothesized that pro-NGF and its p75 neurotrophin receptor (p75NTR) contribute to disrupting adult hippocampal neurogenesis during AD. To test this hypothesis, in this study, we took advantage of the availability of mouse models of AD (APP/PS1), which display memory impairment, and AD human samples to address the role of pro-NGF/p75NTR signaling in different aspects of adult neurogenesis. First, we observed that DG doublecortin (DCX) + progenitors express p75NTR both, in healthy humans and control animals, although the percentage of DCX+ cells are significantly reduced in AD. Interestingly, the expression of p75NTR in these progenitors is significantly decreased in AD conditions compared to controls. In order to assess the contribution of the pro-NGF/p75NTR pathway to the memory deficits of APP/PS1 mice, we injected pro-NGF neutralizing antibodies (anti-proNGF) into the DG of control and APP/PS1 mice and animals are subjected to a Morris water maze test. Intriguingly, we observed that anti-pro-NGF significantly restored memory performance of APP/PS1 animals and significantly increase the percentage of DCX+ progenitors in the DG region of these animals. In summary, our results suggest that pro-NGF is involved in disrupting spatial memory in AD, at least in part by blocking adult neurogenesis. Moreover, we propose that adult neurogenesis alteration should be taken into consideration for better understanding of AD pathology. Additionally, we provide a new molecular entry point (pro-NGF/p75NTR signaling) as a promising therapeutic target in AD. [ABSTRACT FROM AUTHOR]

At advanced stages of Alzheimer’s disease, cognitive dysfunction is accompanied by severe alterations of hippocampal circuits that may largely underlie memory impairments. However, it is likely that anatomical remodeling in the hippocampus may start long before any cognitive alteration is detected. Using the well-described Tg2576 mouse model of Alzheimer’s disease that develops progressive age-dependent amyloidosis and cognitive deficits, we examined whether specific stages of the disease were associated with the expression of anatomical markers of hippocampal dysfunction. We found that these mice develop a complex pattern of changes in their dentate gyrus with aging. Those include aberrant expression of neuropeptide Y and reduced levels of calbindin, reflecting a profound remodeling of inhibitory and excitatory circuits in the dentate gyrus. Preceding these changes, we identified severe alterations of adult hippocampal neurogenesis in Tg2576 mice. We gathered converging data in Tg2576 mice at young age, indicating impaired maturation of new neurons that may compromise their functional integration into hippocampal circuits. Thus, disruption of adult hippocampal neurogenesis occurred before network remodeling in this mouse model and therefore may account as an early event in the etiology of Alzheimer’s pathology. Ultimately, both events may constitute key components of hippocampal dysfunction and associated cognitive deficits occurring in Alzheimer’s disease. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and impaired cognitive functions. The higher incidence of AD among women indicates that sex is one of the main risk factor for developing the disease. Using the transgenic amyloid precursor protein × presenilin 1 (APPxPS1) mouse model of AD, we investigated sex inequality with regards to memory capacities and hippocampal plasticity. We report that spatial memory is strongly affected in APPxPS1 females while remarkably spared in males, at all ages tested. Given the contribution of adult neurogenesis to hippocampal-dependent memory processes, we examined whether impaired neurogenesis could account for age-related decline of memory functions in APPxPS1 mice. We show that not only limited numbers of new neurons are generated in these mice, but also, that new granule cells display reduced capacity for synaptic connectivity, a default that is exacerbated in females. Moreover, high densities of hypertrophic astrocytes are observed in the dentate gyrus of APPxPS1 females specifically. By revealing sex-dependent hippocampal alterations, our data may provide causal explanation to APPxPS1 females' memory deficits. [ABSTRACT FROM AUTHOR]

Adult hippocampal neurogenesis is strongly impaired in Alzheimer's disease (AD). In several mouse models of AD, it was shown that adult-born neurons exhibit reduced survival and altered synaptic integration due to a severe lack of dendritic spines. In the present work, using the APPxPS1 mouse model of AD, we reveal that this reduced number of spines is concomitant of a marked deficit in their neuronal mitochondrial content. Remarkably, we show that targeting the overexpression of the pro-neural transcription factor Neurod1 into APPxPS1 adult-born neurons restores not only their dendritic spine density, but also their mitochondrial content and the proportion of spines associated with mitochondria. Using primary neurons, a bona fide model of neuronal maturation, we identified that increases of mitochondrial respiration accompany the stimulating effect of Neurod1 overexpression on dendritic growth and spine formation. Reciprocally, pharmacologically impairing mitochondria prevented Neurod1 -dependent trophic effects. Thus, since overexpression of Neurod1 into new neurons of APPxPS1 mice rescues spatial memory, our present data suggest that manipulating the mitochondrial system of adult-born hippocampal neurons provides neuronal plasticity to the AD brain. These findings open new avenues for far-reaching therapeutic implications towards neurodegenerative diseases associated with cognitive impairment. [ABSTRACT FROM AUTHOR]