María Llorens-Martín

Reviews: Mechanisms Mediating Brain Plasticity: IGF1 and Adult Hippocampal Neurogenesis:

This review addresses the role of serum insulin-like growth factor 1 (IGF1) as one mechanism of adult neural plasticity, specifically, its regulation of hippocampal neurogenesis among other plasticity-related processes. It is suggested that IGF has been reused advantageously both for the control of energy expenditure as a function of the organisms activity and to protect, repair, and plastically modulate the brain. Moreover, because as the main source of IGF1 in the adult organism is outside the brain and its presence in this organ is a function of the activity, IGF1 becomes an ideal factor to induce plastic/neuroprotective functions as a function of the organisms activity. The link for this point of view comes from the original function of IGF1 during ontogeny/phylogeny, the promotion of cell survival and control of neural cell numbers, whereas one of the IGF1 functions in the adult brain is the control of hippocampal neurogenesis. The investigation of the IGF1 role as mediator of exercise effects suggests that many but not all the effects of physical activity are mediated by IGF1. These investigations have contributed to delimit the role of IGF1 as mediator of exercise actions, but at the same time are unveiling new roles for serum IGF1 inside the brain.

Exercise modulates insulin-like growth factor 1-dependent and -independent effects on adult hippocampal neurogenesis and behaviour

While physical exercise clearly has beneficial effects on the brain, fomenting neuroprotection as well as promoting neural plasticity and behavioural modifications, the cellular and molecular mechanisms mediating these effects are not yet fully understood. We have analyzed sedentary and exercised animals to examine the effects of activity on behaviour (spatial memory and anxiety--as measured by a fear/exploration conflict test), as well as on adult hippocampal neurogenesis (a well-known form of neural plasticity). We have found that the difference in activity between sedentary and exercised animals induced a decrease in the fear/exploration conflict scores (a measure usually accepted as an anxiolytic effect), while no changes are evident in terms of spatial memory learning. The short-term anxiolytic-like effect of exercise was IGF1-dependent and indeed, the recall of hippocampus-dependent spatial memory is impaired by blocking serum IGF1 (as observed by measuring serum IGF levels in the same animals used to analyze the behaviour), irrespective of the activity undertaken by the animals. On the other hand, activity affected neurogenesis as reflected by counting the numbers of several cell populations, while the dependence of this effect on IGF1 varied according to the differentiation state of the new neurons. Hence, while proliferating precursors and postmitotic immature neurons (measured by means of doublecortin and calretinin) are influenced by serum IGF1 levels in both sedentary and exercised animals, premitotic immature neurons (an intermediate stage) respond to exercise independently of serum IGF1. Therefore, we conclude that physical exercise has both serum IGF1-independent and -dependent effects on neural plasticity. Furthermore, several effects mediated by serum IGF1 are induced by physical activity while others are not (both in terms of behaviour and neural plasticity). These findings help to delimit the role of serum IGF1 as a mediator of the effects of exercise, as well as to extend the role of serum IGF1 in the brain in basal conditions. Moreover, these data reveal the complexity of the interaction between neurogenesis, behaviour, and IGF1 under different levels of physical activity.

Memantine Normalizes Several Phenotypic Features in the Ts65Dn Mouse Model of Down Syndrome

Ts65Dn (TS) mice exhibit several phenotypic characteristics of human Down syndrome, including an increased brain expression of amyloid-beta protein precursor (AbetaPP) and cognitive disturbances. Aberrant N-methyl-D-aspartate (NMDA) receptor signaling has been suspected in TS mice, due to an impaired generation of hippocampal long-term potentiation (LTP). Memantine, an uncompetitive NMDA receptor antagonist approved for the treatment of moderate to severe Alzheimers disease, is known to normalize LTP and improve cognition in transgenic mice with high brain levels of AbetaPP and amyloid-beta protein. It has recently been demonstrated that acute injections of memantine rescue performance deficits of TS mice on a fear conditioning test. Here we show that oral treatment of aged TS mice with a clinically relevant dose of memantine (30 mg/kg/day for 9 weeks) improved spatial learning in the water maze task and slightly reduced brain AbetaPP levels. We also found that TS mice exhibited a significantly reduced granule cell count and vesicular glutamate transporter-1 (VGLUT1) labeling compared to disomic control mice. After memantine treatment, the levels of hippocampal VGLUT1 were significantly increased, reaching the levels observed in vehicle treated-control animals. Memantine did not significantly affect granule cell density. These data indicate that memantine may normalize several phenotypic abnormalities in TS mice, many of which--such as impaired cognition--are also associated with Down syndrome and Alzheimers disease.

Role of neuroinflammation in adult neurogenesis and Alzheimer disease: Therapeutic approaches

Neuroinflammation, a specialized immune response that takes place in the central nervous system, has been linked to neurodegenerative diseases, and specially, it has been considered as a hallmark of Alzheimer disease, the most common cause of dementia in the elderly nowadays. Furthermore, neuroinflammation has been demonstrated to affect important processes in the brain, such as the formation of new neurons, commonly known as adult neurogenesis. For this, many therapeutic approaches have been developed in order to avoid or mitigate the deleterious effects caused by the chronic activation of the immune response. Considering this, in this paper we revise the relationships between neuroinflammation, Alzheimer disease, and adult neurogenesis, as well as the current therapeutic approaches that have been developed in the field.

Blockade of Insulin-Like Growth Factor-I Has Complex Effects on Structural Plasticity in the Hippocampus

Physical exercise enhances adult neurogenesis in the hippocampus. Running induces the uptake of blood insulin‐like growth factor‐I (IGF‐I) into the brain. A causal link between these two phenomena has been reported; running‐induced increases in adult neurogenesis can be blocked by peripheral infusion of anti‐IGF‐I. Running also alters other aspects of hippocampal structure, including dendritic spine density. It remains unclear, however, whether these effects are also mediated through an IGF‐I mechanism. To examine this possibility, we blocked peripheral IGF‐I and examined adult neurogenesis and dendritic spine density in treadmill running mice. Two weeks of running resulted in an increase in cell proliferation in the dentate gyrus (DG) as well as an increase in dendritic spine density on DG granule cells and basal dendrites of CA1 pyramidal neurons, while having no effect on apical or basal dendritic spine density of CA3 pyramidal neurons. IGF‐I blockade reduced cell proliferation in both sedentary and running mice, but by contrast, this treatment had no effect on granule cell or CA3 pyramidal cell dendritic spine density in sedentary or running mice. However, IGF‐I antibody treatment seemed to prevent the running‐induced increase in spine density on basal dendrites of CA1 pyramidal cells. These results suggest that IGF‐I exerts a complex influence over hippocampal structure and that its effects are not restricted to those induced by running.

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.

Growth Factors as Mediators of Exercise Actions on the Brain

Physical exercise has long been recognized as highly beneficial for brain and body health. The molecular mechanisms responsible for translation of exercise stimuli in the brain have claimed attention due to mounting evidence for the neuroprotective actions of the exercise and its positive effects in preventing both ageing and neurodegenerative disease. These molecular mediators are currently under investigation with new tools able to yield deep insights into the neurobiology of exercise. In the present work we focus on the evidence pertaining to the mediation of exercise effects by insulin-like growth factor 1 (IGF1), as recent reports suggest that this growth factor shows brain area-specific, temporal rank-sensitive, and behavioural task-dependent features in response to exercise.

Tau Protein and Adult Hippocampal Neurogenesis

Tau protein is a microtubule-associated protein found in the axonal compartment that stabilizes neuronal microtubules under normal physiological conditions. Tau metabolism has attracted much attention because of its role in neurodegenerative disorders called tauopathies, mainly Alzheimer disease. Here, we review recent findings suggesting that axonal outgrowth in subgranular zone during adult hippocampal neurogenesis requires a dynamic microtubule network and tau protein facilitates to maintain that dynamic cytoskeleton. Those functions are carried out in part by tau isoform with only three microtubule-binding domains (without exon 10) and by presence of hyperphosphorylated tau forms. Thus, tau is a good marker and a valuable tool to study new axons in adult neurogenesis.

Dual effects of increased glycogen synthase kinase-3β activity on adult neurogenesis

Adult neurogenesis, the generation of new neurons during the adulthood, is a process controlled by several kinases and phosphatases among which GSK3β exerts important functions. This protein is particularly abundant in the central nervous system, and its activity deregulation is believed to play a key role in chronic disorders such as Alzheimers disease. Previously, we reported that in vivo overexpression of GSK3β (Tet/GSK3β mice) causes alterations in adult neurogenesis, leading to a depletion of the neurogenic niches. Here, we have further characterized those alterations, finding a delay in the switching-off of doublecortin marker as well as changes in the survival and death rates of immature precursors and a decrease in the total number of mature neurons. Besides, we have highlighted the importance of the inflammatory environment, identifying eotaxin as a possible modulator of the detrimental effects on adult neurogenesis. Taking advantage of the conditional system, we have also explored whether these negative consequences of increasing GSK3 activity are susceptible to revert after doxycycline treatment. We show that transgene shutdown in symptomatic mice reverts microgliosis, abnormal eotaxin levels as well as the aforementioned alterations concerning immature neurons. Unexpectedly, the decrease in the number of mature neurons and neuronal precursor cells of the subgranular zone of Tet/GSK3β mice could not be reverted. Thus, alterations in adult neurogenesis and likely in neurodegenerative disorders can be restored in part, although neurogenic niche depletion represents a non-reversible damage persisting during lifetime with a remarkable impact in adult mature neurons.

Different Susceptibility to Neurodegeneration of Dorsal and Ventral Hippocampal Dentate Gyrus: A Study with Transgenic Mice Overexpressing GSK3β

Dorsal hippocampal regions are involved in memory and learning processes, while ventral areas are related to emotional and anxiety processes. Hippocampal dependent memory and behaviour alterations do not always come out in neurodegenerative diseases at the same time. In this study we have tested the hypothesis that dorsal and ventral dentate gyrus (DG) regions respond in a different manner to increased glycogen synthase kinase-3β (GSK3β) levels in GSK3β transgenic mice, a genetic model of neurodegeneration. Reactive astrocytosis indicate tissue stress in dorsal DG, while ventral area does not show that marker. These changes occurred with a significant reduction of total cell number and with a significantly higher level of cell death in dorsal area than in ventral one as measured by fractin-positive cells. Biochemistry analysis showed higher levels of phosphorylated GSK3β in those residues that inactivate the enzyme in hippocampal ventral areas compared with dorsal area suggesting that the observed susceptibility is in part due to different GSK3 regulation. Previous studies carried out with this animal model had demonstrated impairment in Morris Water Maze and Object recognition tests point out to dorsal hippocampal atrophy. Here, we show that two tests used to evaluate emotional status, the light–dark box and the novelty suppressed feeding test, suggest that GSK3β mice do not show any anxiety-related disorder. Thus, our results demonstrate that in vivo overexpression of GSK3β results in dorsal but not ventral hippocampal DG neurodegeneration and suggest that both areas do not behave in a similar manner in neurodegenerative processes.