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 adultgenerated 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. © 2012 the authors.This project was supported by Grant BFU2008-3980 from the Ministerio de Ciencia e Innovación (MICINN), Spain; by grants from the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) and Caixa Catalunya-Obra Social Foundations to E.S.; by grants from the Spanish Ministry of Science and Innovation (SAF2009-07367 and CONSOLIDER CSD2007-00023) to V.B.; by the Fred Annegers Fellowship from the Epilepsy Foundation (M.M.K.); and by NIH Grant NS058585 to J.M.P. I.R. was recipient of a Formación de Personal Universitario predoctoral fellowship from MINECO (Spain).Peer Reviewe

Abnormal Serotonin Levels During Perinatal Development Lead to Behavioral Deficits in Adulthood

Serotonin (5-HT) is one of the best-studied modulatory neurotransmitters with ubiquitous presynaptic release and postsynaptic reception. 5-HT has been implicated in a wide variety of brain functions, ranging from autonomic regulation, sensory perception, feeding and motor function to emotional regulation and cognition. The role of this neuromodulator in neuropsychiatric diseases is unquestionable with important neuropsychiatric medications, e.g., most antidepressants, targeting this system. Importantly, 5-HT modulates neurodevelopment and changes in its levels during development can have life-long consequences. In this mini-review, we highlight that exposure to both low and high serotonin levels during the perinatal period can lead to behavioral deficits in adulthood. We focus on three exogenous factors that can change 5-HT levels during the critical perinatal period: dietary tryptophan depletion, exposure to serotonin-selective-reuptake-inhibitors (SSRIs) and poor early life care. We discuss the effects of each of these on behavioral deficits in adulthood

Versatile use of rtTA-expressing retroviruses in the study of neurodegeneration

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Abnormal Serotonin Levels During Perinatal Development Lead to Behavioral Deficits in Adulthood

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Untold New Beginnings: Adult Hippocampal Neurogenesis and Alzheimer's Disease

Neurogenesis occurs in a limited number of brain regions during adulthood. Of these, the hippocampus has attracted great interest due to its involvement in memory processing. Moreover, both the hippocampus and the main area that innervates this structure, namely the entorhinal cortex, show remarkable atrophy in patients with Alzheimer's disease (AD). Adult hippocampal neurogenesis is a process that continuously gives rise to newborn granule neurons in the dentate gyrus. These cells coexist with developmentally generated granule neurons in this structure, and both cooperative and competition phenomena regulate the communication between these two types of cells. Importantly, it has been revealed that GSK-3β and tau proteins, which are two of the main players driving AD pathology, are cornerstones of adult hippocampal neurogenesis regulation. We have shown that alterations either promoting or impeding the actions of these two proteins have detrimental effects on the structural plasticity of granule neurons. Of note, these impairments occur both under basal conditions and in response to detrimental and neuroprotective stimuli. Thus, in order to achieve the full effectiveness of future therapies for AD, we propose that attention be turned toward identifying the pathological and physiological actions of the proteins involved in the pathogenesis of this condition.Spanish Ministry of Economy and Competitiveness (SAF-2014-53040-P (Jesu´s A´ vila) and RYC-2015-17189 (María Llorens-Mart´ın)); the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain) (Jesu´s Avila); the Alzheimer’s Association (2015-NIRG-340709 (Mar´ıa Llorens-Mart´ın)); and the Association for Frontotemporal Degeneration (2016 Basic Science Pilot Grant Award (María Llorens-Martín))

Retroviral induction of GSK-3β expression blocks the stimulatory action of physical exercise on the maturation of newborn neurons

Adult hippocampal neurogenesis (AHN) is a key process for certain types of hippocampal-dependent learning. Alzheimer’s disease (AD) is accompanied by memory deficits related to alterations in AHN. Given that the increased activity of GSK-3β has been related to alterations in the population of hippocampal granule neurons in AD patients, we designed a novel methodology by which to induce selective GSK-3β overexpression exclusively in newborn granule neurons. To this end, we injected an rtTA-IRES-EGFP-expressing retrovirus into the hippocampus of tTO-GSK-3β mice. Using this novel retroviral strategy, we found that GSK-3β caused a cell-autonomous impairment of the morphological and synaptic maturation of newborn neurons. In addition, we examined whether GSK-3β overexpression in newborn neurons limits the effects of physical activity. While physical exercise increased the number of dendritic spines, the percentage of mushroom spines, and the head diameter of the same in tet-OFF cells, these effects were not triggered in tet-ON cells. This observation suggests that GSK-3β blocks the stimulatory actions of exercise. Given that the activity of GSK-3β is increased in the brains of individuals with AD, these data may be relevant for non-pharmacological therapies for AD.Spanish Ministry of Health (SAF-2014-5040-P), and the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII) (J. A ´ vila); the Japan Society for the promotion of Science (post-doctoral fellowship to M. Llorens-Martín); and the Alzheimer’s Association (2015-NIRG-34070

GSK-3β overexpression causes reversible alterations on postsynaptic densities and dendritic morphology of hippocampal granule neurons in vivo

Adult hippocampal neurogenesis (AHN) is crucial for the maintenance of hippocampal function. Several neurodegenerative diseases such as Alzheimer's disease (AD) are accompanied by memory deficits that could be related to alterations in AHN. Here, we took advantage of a conditional mouse model to study the involvement of glycogen synthase kinase-3β (GSK-3β) overexpression (OE) in AHN. By injecting GFP- and PSD95-GFP-expressing retroviruses, we have determined that hippocampal GSK-3β-OE causes dramatic alterations in both dendritic tree morphology and post-synaptic densities in newborn neurons. Alterations in previously damaged neurons were reverted by switching off the transgenic system and also by using a physiological approach (environmental enrichment) to increase hippocampal plasticity. Furthermore, comparative morphometric analysis of granule neurons from patients with AD and from GSK-3β overexpressing mice revealed shared morphological alterations. Taken together, these data indicate that GSK-3β is crucial for hippocampal function, thereby supporting this kinase as a relevant target for the treatment of AD. © 2013 Macmillan Publishers Limited.Spanish Ministry of Health (SAF 2006-02424, BFU-2008-03980 and BFU-2010-21507); the Comunidad de Madrid (SAL/0202/2006); Fundación M. Botín; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII); Fundación R Areces.Peer Reviewe

Alzheimer disease-like cellular phenotype of newborn granule neurons can be reversed in GSK-3β-overexpressing mice

In the dentate gyrus of wild-type (wt) mice (a), neuronal precursors maturate and differentiate into mature granule neurons under the influence of pro-neurogenic molecules, such as neurotrophic factors and anti-inflammatory cytokines. In glycogen synthase kinase 3 (GSK-3b)-overexpressing mice (GSK-3b-OE mice) (b), increased neuronal death activates microglia and increases pro-inflammatory cytokine (affecting early neuronal precursor development, as an indirect consequence of GSK-3b overexpression). Throughout the maturational process, morphological alterations are observed in granule neurons of GSK-3b-OE mice. In addition, as a direct consequence of GSK-3b-OE, these cells experience a dramatic reduction of postsynaptic cluster number and volume. Doxycycline treatment did not produce any significant effect on wt mice (c), whereas it successfully reverted the aberrant morphology of granule neurons and normalized pro-inflammatory cytokine levels in GSK-3b-OE mice (d). In addition, the restoration of normal levels of GSK-3b activity produced a drastic increase in the number of postsynaptic clusters (d). The number of postsynaptic clusters is drastically increased in wt mice after environmental enrichment (EE) (e). It is important to note that, in wt mice, EE particularly increased the number of small, newly developed, synaptic contacts, whereas postsynaptic cluster size was increased in GSK-3b-OE animals after EE (f), potentially contributing to enhanced synaptic strength. Interestingly, both doxycycline treatment and EE restored the increased number of ‘pathological’ microglial cells and also normalized pro-inflammatory cytokines to basal levels in GSK-3b-OE mice, thus allowing newborn neurons to develop appropriate morphology and connectivity.Peer Reviewe