Increased neuronal excitability, synaptic plasticity, and learning in aged Kvbeta1.1 knockout mice

BACKGROUND: Advancing age is typically accompanied by deficits in learning and memory. These deficits occur independently of overt pathology and are often considered to be a part of "normal aging." At the neuronal level, normal aging is known to be associated with numerous cellular and molecular changes, which include a pronounced decrease in neuronal excitability and an altered induction in the threshold for synaptic plasticity. Because both of these mechanisms (neuronal excitability and synaptic plasticity) have been implicated as putative cellular substrates for learning and memory, it is reasonable to propose that age-related changes in these mechanisms may contribute to the general cognitive decline that occurs during aging. RESULTS: To further investigate the relationship between aging, learning and memory, neuronal excitability, and synaptic plasticity, we have carried out experiments with aged mice that lack the auxiliary potassium channel subunit Kvbeta1.1. In aged mice, the deletion of the auxiliary potassium channel subunit Kvbeta1.1 resulted in increased neuronal excitability, as measured by a decrease in the post-burst afterhyperpolarization. In addition, long-term potentiation (LTP) was more readily induced in aged Kvbeta1.1 knockout mice. Finally, the aged Kvbeta1.1 mutants outperformed age-matched controls in the hidden-platform version of the Morris water maze. Interestingly, the enhancements in excitability and learning were both sensitive to genetic background: The enhanced learning was only observed in a genetic background in which the mutants exhibited increased neuronal excitability. CONCLUSIONS: Neuronal excitability is an important determinant of both synaptic plasticity and learning in aged subjects.     

Evolution of the aging brain transcriptome and synaptic regulation

Alzheimer's disease and other neurodegenerative disorders of aging are characterized by clinical and pathological features that are relatively specific to humans. To obtain greater insight into how brain aging has evolved, we compared age-related gene expression changes in the cortex of humans, rhesus macaques, and mice on a genome-wide scale. A small subset of gene expression changes are conserved in all three species, including robust age-dependent upregulation of the neuroprotective gene apolipoprotein D (APOD) and downregulation of the synaptic cAMP signaling gene calcium/calmodulin-dependent protein kinase IV (CAMK4). However, analysis of gene ontology and cell type localization shows that humans and rhesus macaques have diverged from mice due to a dramatic increase in age-dependent repression of neuronal genes. Many of these age-regulated neuronal genes are associated with synaptic function. Notably, genes associated with GABA-ergic inhibitory function are robustly age-downregulated in humans but not in mice at the level of both mRNA and protein. Gene downregulation was not associated with overall neuronal or synaptic loss. Thus, repression of neuronal gene expression is a prominent and recently evolved feature of brain aging in humans and rhesus macaques that may alter neural networks and contribute to age-related cognitive changes.     

Trimethylamine‐N‐oxide promotes brain aging and cognitive impairment in mice

Gut microbiota can influence the aging process and may modulate aging‐related changes in cognitive function. Trimethylamine‐N‐oxide (TMAO), a metabolite of intestinal flora, has been shown to be closely associated with cardiovascular disease and other diseases. However, the relationship between TMAO and aging, especially brain aging, has not been fully elucidated. To explore the relationship between TMAO and brain aging, we analysed the plasma levels of TMAO in both humans and mice and administered exogenous TMAO to 24‐week‐old senescence‐accelerated prone mouse strain 8 (SAMP8) and age‐matched senescence‐accelerated mouse resistant 1 (SAMR1) mice for 16 weeks. We found that the plasma levels of TMAO increased in both the elderly and the aged mice. Compared with SAMR1‐control mice, SAMP8‐control mice exhibited a brain aging phenotype characterized by more senescent cells in the hippocampal CA3 region and cognitive dysfunction. Surprisingly, TMAO treatment increased the number of senescent cells, which were primarily neurons, and enhanced the mitochondrial impairments and superoxide production. Moreover, we observed that TMAO treatment increased synaptic damage and reduced the expression levels of synaptic plasticity‐related proteins by inhibiting the mTOR signalling pathway, which induces and aggravates aging‐related cognitive dysfunction in SAMR1 and SAMP8 mice, respectively. Our findings suggested that TMAO could induce brain aging and age‐related cognitive dysfunction in SAMR1 mice and aggravate the cerebral aging process of SAMP8 mice, which might provide new insight into the effects of intestinal microbiota on the brain aging process and help to delay senescence by regulating intestinal flora metabolites.     

Chelation of hippocampal zinc enhances long‐term potentiation and synaptic tagging/capture in CA1 pyramidal neurons of aged rats: implications to aging and memory

Aging is associated with decline in cognitive functions, prominently in the memory consolidation and association capabilities. Hippocampus plays a crucial role in the formation and maintenance of long‐term associative memories, and a significant body of evidence shows that impairments in hippocampal function correlate with aging‐related memory loss. A number of studies have implicated alterations in hippocampal synaptic plasticity, such as long‐term potentiation (LTP), in age‐related cognitive decline although exact mechanisms underlying are not completely clear. Zinc deficiency and the resultant adverse effects on cognition have been well studied. However, the role of excess of zinc in synaptic plasticity, especially in aging, is not addressed well. Here, we have investigated the hippocampal zinc levels and the impairments in synaptic plasticity, such as LTP and synaptic tagging and capture (STC), in the CA1 region of acute hippocampal slices from 82‐ to 84‐week‐old male Wistar rats. We report increased zinc levels in the hippocampus of aged rats and also deficits in the tetani‐induced and dopaminergic agonist‐induced late‐LTP and STC. The observed deficits in synaptic plasticity were restored upon chelation of zinc using a cell‐permeable chelator. These data suggest that functional plasticity and associativity can be successfully established in aged neural networks by chelating zinc with cell‐permeable chelating agents.     

Molecular Bases of Caloric Restriction Regulation of Neuronal Synaptic Plasticity

Aging is associated with the decline of cognitive properties. This situation is magnified when neurodegenerative processes associated with aging appear in human patients. Neuronal synaptic plasticity events underlie cognitive properties in the central nervous system. Caloric restriction (CR; either a decrease in food intake or an intermittent fasting diet) can extend life span and increase disease resistance. Recent studies have shown that CR can have profound effects on brain function and vulnerability to injury and disease. Moreover, CR can stimulate the production of new neurons from stem cells (neurogenesis) and can enhance synaptic plasticity, which modulate pain sensation, enhance cognitive function, and may increase the ability of the brain to resist aging. The beneficial effects of CR appear to be the result of a cellular stress response stimulating the production of proteins that enhance neuronal plasticity and resistance to oxidative and metabolic insults; they include neurotrophic factors, neurotransmitter receptors, protein chaperones, and mitochondrial biosynthesis regulators. In this review, we will present and discuss the effect of CR in synaptic processes underlying analgesia and cognitive improvement in healthy, sick, and aging animals. We will also discuss the possible role of mitochondrial biogenesis induced by CR in regulation of neuronal synaptic plasticity.     

Structural plasticity of synapses in Alzheimer's disease

Plasticity of the synaptic contact zone was previously observed following loss of synapses in the cerebral cortex of normal aging humans. The present study was undertaken to determine if there was quantitative evidence of synapse loss and synapse plasticity in the inferior temporal, superior parietal, parieto-occipital, and superior frontal cortical regions in Alzheimer's disease (AD), and how such changes related to the neurofibrillary tangles and amyloid plaques. The results showed that age at autopsy did not correlate with the numbers of synapses, plaques, or tangles. However, the numbers of synapses strongly reflected the pathology of AD; in all four brain regions, there were fewer synapses as the numbers of plaques and tangles increased. In the inferior temporal and superior parietal cortices, the loss of synapses was accompanied by an increase in the synaptic contact length. The results suggest that, in some cerebral cortical brain regions, synapses are capable of plasticity changes, even when the pathology of AD and loss of synapses are severe.     

A critical role for the glial-derived neuromodulator D-serine in the age-related deficits of cellular mechanisms of learning and memory

Age-associated deficits in learning and memory are closely correlated with impairments of synaptic plasticity. Analysis of N-methyl-D-aspartate receptor (NMDAr)-dependent long-term potentiation (LTP) in CA1 hippocampal slices indicates that the glial-derived neuromodulator D-serine is required for the induction of synaptic plasticity. During aging, the content of D-serine and the expression of its synthesizing enzyme serine racemase are significantly decreased in the hippocampus. Impaired LTP and NMDAr-mediated synaptic potentials in old rats are rescued by exogenous D-serine. These results highlight the critical role of glial cells and presumably astrocytes, through the availability of D-serine, in the deficits of synaptic mechanisms of learning and memory that occur in the course of aging.     

Absent in melanoma 2 mediates aging-related cognitive dysfunction by acting on complement-dependent microglial phagocytosis

Pattern separation (PS) dysfunction is a type of cognitive impairment that presents early during the aging process, and this deficit has been attributed to structural and functional alterations in the dentate gyrus (DG) of the hippocampus. Absent in melanoma 2 (AIM2) is an essential component of the inflammasome. However, whether AIM2 plays a role in aging-associated cognitive dysfunction remains unclear. Here, we found that PS function was impaired in aging mice and was accompanied by marked synaptic loss and increased expression of AIM2 in the DG. Subsequently, we used an AIM2 overexpression virus and mice with AIM2 deletion to investigate the role of AIM2 in regulating PS function and synaptic plasticity and the mechanisms involved. Our study revealed that AIM2 regulates microglial activation during synaptic pruning in the DG region via the complement pathway, leading to impaired synaptic plasticity and PS function in aging mice. These results suggest a critical role for AIM2 in regulating synaptic plasticity and PS function and provide a new direction for ameliorating aging-associated cognitive dysfunction.     

7,8-dihydroxyflavone rescues spatial memory and synaptic plasticity in cognitively impaired aged rats

7,8-dihydroxyflavone (7,8-DHF) has recently been identified as a potential TrkB agonist that crosses the blood-brain barrier after i.p. administration. We previously demonstrated that 7,8-DHF in vitro rescues long-term synaptic plasticity in the hippocampus of aged rats. This study assessed the rescue effect of 7,8-DHF in vivo on aging-related cognitive impairment in rats, and further determined whether the effect of 7,8-DHF is age dependent. Aged rats at 22 and 30 months of age were pretested for spatial memory in Morris water maze. The aged-impaired rats were retested twice during 7,8-DHF or vehicle treatment, which started 3 weeks after the completion of the pretest. In the 22-month-old rats, daily i.p. administration of 7,8-DHF for 2 weeks improved spatial memory. The improvement in behavioral tests was associated with increases in synapse formation and facilitation of synaptic plasticity in the hippocampus, as well as the activation of several proteins crucial to synaptic plasticity and memory. A more extended treatment paradigm with 7,8-DHF was required to achieve a significant memory improvement in the severely impaired 30-month-old rats. Moreover, 7,8-DHF moderately facilitated the synaptic plasticity, modified the density but not number of spines in the hippocampus of the oldest rats. Taken together, our results suggest that 7,8-DHF can act in vivo to counteract aging-induced declines in spatial memory and synaptic plasticity and morphological changes of hippocampal neurons. The effect of 7,8-DHF is more pronounced in relatively younger impaired rats than in those of more advanced age. These findings demonstrate the reversal of age-dependent memory impairment by in vivo 7,8-DHF application and support the benefit of early treatment for cognitive aging.     

Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons

Drug seeking and drug self-administration in both animals and humans can be triggered by drugs of abuse themselves or by stressful events. Here, we demonstrate that in vivo administration of drugs of abuse with different molecular mechanisms of action as well as acute stress both increase strength at excitatory synapses on midbrain dopamine neurons. Psychoactive drugs with minimal abuse potential do not cause this change. The synaptic effects of stress, but not of cocaine, are blocked by the glucocorticoid receptor antagonist RU486. These results suggest that plasticity at excitatory synapses on dopamine neurons may be a key neural adaptation contributing to addiction and its interactions with stress and thus may be an attractive therapeutic target for reducing the risk of addiction.     

The Interplay of Oxygen Functional Groups and Folded Texture in Densified Graphene Electrodes for Compact Sodium‐Ion Capacitors

Sodium‐ion capacitors (SICs) can effectively combine high energy density with high power density, and are especially appropriate for high‐power demanding applications of large‐scale stationary energy storage. Surface‐induced pseudocapacitive charge storage based on porous or nano carbon materials is regarded as the most promising candidate for SICs. Unfortunately, their ultralow packing densities severely restrict their practical applications. A novel approach toward ultrafast high‐volumetric SICs based on folded‐graphene electrodes has already been demonstrated and showed quite competitive performance. In this work, it is further proved that oxygen functional groups and folded texture are two key elements for high‐volumetric sodium storage of folded‐graphene electrodes. Through a simple and controllable method, of thermal treatment in inert atmosphere, both the oxygen functional groups and folded texture can be quantitatively manipulated to better investigate the individual contribution and mutual interplay. It is illustrated that oxygen functional groups are crucial to superior capacitive sodium storage while folded texture is not only the origin for high‐volumetric sodium storage but also beneficial for both capacitive and additional diffusion‐controlled sodium storage. Inspired by above‐mentioned conclusion, more rational designs and effective preparation of advanced structure and novel materials can be realized to better promote the development of high‐volumetric SICs.     

Presynaptic plasticity and associative learning are impaired in a Drosophila presenilin null mutant

Alzheimer's disease is a neurodegenerative disorder characterized by progressive memory and cognitive decline that is associated with changes in synaptic plasticity and neuronal cell loss. Recent evidence suggests that some of these defects may be due to a loss of normal presenilin activity. Here, we have examined the effect of loss of Drosophila presenilin (psn) function on synaptic plasticity and learning. Basal transmitter release was elevated in psn mutants while both paired pulse synaptic plasticity and post-tetanic potentiation were impaired. These defects in synaptic strength and plasticity were not due to developmental defects in NMJ morphology. We also found that psn null terminals take up significantly less FM 4-64 than control terminals when loaded with high frequency stimulation, suggesting a defect in synaptic vesicle availability or mobilization. To determine whether these reductions in synaptic plasticity had any impact on learning, we tested the larvae for defects in associative learning. Using both olfactory and visual learning assays, we found that associative learning is impaired in psn mutants compared with controls. Both the learning and synaptic defects could be rescued by expression of a full length psn transgene suggesting the defects are specifically due to a loss of psn function. Taken together, these results provide the first evidence of learning and synaptic defects in a Drosophila psn mutant and strongly suggest a presynaptic role for presenilin in normal neuronal function.     

Pre- and postsynaptically expressed spike-timing-dependent plasticity contribute differentially to neuronal learning

A plethora of experimental studies have shown that long-term synaptic plasticity can be expressed pre- or postsynaptically depending on a range of factors such as developmental stage, synapse type, and activity patterns. The functional consequences of this diversity are not clear, although it is understood that whereas postsynaptic expression of plasticity predominantly affects synaptic response amplitude, presynaptic expression alters both synaptic response amplitude and short-term dynamics. In most models of neuronal learning, long-term synaptic plasticity is implemented as changes in connective weights. The consideration of long-term plasticity as a fixed change in amplitude corresponds more closely to post- than to presynaptic expression, which means theoretical outcomes based on this choice of implementation may have a postsynaptic bias. To explore the functional implications of the diversity of expression of long-term synaptic plasticity, we adapted a model of long-term plasticity, more specifically spike-timing-dependent plasticity (STDP), such that it was expressed either independently pre- or postsynaptically, or in a mixture of both ways. We compared pair-based standard STDP models and a biologically tuned triplet STDP model, and investigated the outcomes in a minimal setting, using two different learning schemes: in the first, inputs were triggered at different latencies, and in the second a subset of inputs were temporally correlated. We found that presynaptic changes adjusted the speed of learning, while postsynaptic expression was more efficient at regulating spike timing and frequency. When combining both expression loci, postsynaptic changes amplified the response range, while presynaptic plasticity allowed control over postsynaptic firing rates, potentially providing a form of activity homeostasis. Our findings highlight how the seemingly innocuous choice of implementing synaptic plasticity by single weight modification may unwittingly introduce a postsynaptic bias in modelling outcomes. We conclude that pre- and postsynaptically expressed plasticity are not interchangeable, but enable complimentary functions.     

Hippocampal Extracellular Matrix Levels and Stochasticity in Synaptic Protein Expression Increase with Age and Are Associated with Age-dependent Cognitive Decline

Age-related cognitive decline is a serious health concern in our aging society. Decreased cognitive function observed during healthy brain aging is most likely caused by changes in brain connectivity and synaptic dysfunction in particular brain regions. Here we show that aged C57BL/6J wild-type mice have hippocampus-dependent spatial memory impairments. To identify the molecular mechanisms that are relevant to these memory deficits, we investigated the temporal profile of mouse hippocampal synaptic proteome changes at 20, 40, 50, 60, 70, 80, 90, and 100 weeks of age. Extracellular matrix proteins were the only group of proteins that showed robust and progressive up-regulation over time. This was confirmed by immunoblotting and histochemical analysis, which indicated that the increased levels of hippocampal extracellular matrix might limit synaptic plasticity as a potential cause of age-related cognitive decline. In addition, we observed that stochasticity in synaptic protein expression increased with age, in particular for proteins that were previously linked with various neurodegenerative diseases, whereas low variance in expression was observed for proteins that play a basal role in neuronal function and synaptic neurotransmission. Together, our findings show that both specific changes and increased variance in synaptic protein expression are associated with aging and may underlie reduced synaptic plasticity and impaired cognitive performance in old age.As the proportion of aged individuals in our population continues to grow, we are faced with an increase in age-related health problems. Brain aging invariably leads to functional decline and impairments in cognitive function and motor skills, which can seriously affect quality of life. A better understanding of the neurobiological mechanisms underlying age-related cognitive decline is crucial to facilitate maintenance of cognitive health in the elderly and to reveal potential causes of highly prevalent age-related forms of dementia, in particular Alzheimer disease, in which cognitive decline is severely impaired by yet unknown mechanisms.Several studies showed that normal brain aging is associated with subtle morphological and functional alterations in specific neuronal circuits (1, 2) and that reduced cognitive function with increasing age is likely due to synaptic dysfunction (3). Increasing evidence supports the idea that alterations in hippocampal activity are correlated with deficits in learning and memory in healthy aging humans (4, 5). In addition, rodent models of healthy aging demonstrate strong correlations between impaired performance in learning and memory tests and disturbed hippocampal network activity (6, 7). Electrophysiological studies provide additional evidence that age-related disturbances in the hippocampus involve changes in the principal cellular features of learning and memory, synaptic long-term potentiation and long-term depression (8, 9). Together, these observations suggest that a decline in hippocampal synaptic efficacy and plasticity plays a critical role in age-dependent cognitive impairment.Aging is also the primary risk factor for Alzheimer disease, which clinically manifests as severe and accelerated age-dependent cognitive decline (10). Genetic causes of familial early-onset Alzheimer disease all point to a key role in disease etiology for increased brain levels of the protein amyloid-β (11). Familial Alzheimer disease, however, is rare, and it is likely that increased amyloid-β levels in sporadic Alzheimer disease result from age-dependent and/or genetically determined alterations in the expression of other genes or proteins (12, 13). Thus, the identification of molecular mechanisms of normal brain aging might also contribute to our understanding of cognitive decline under pathological conditions, in particular in Alzheimer disease.Although the exact mechanisms underlying brain aging remain to be fully determined, they likely include changes at the molecular, cellular, and neuronal-network levels. In particular, characterization of alterations in the molecular composition and dynamics of hippocampal synapses could potentially reveal important aspects of the underlying mechanisms of brain aging. Age-related changes in global hippocampal gene and protein expression have been investigated previously (14, 15), but these studies were not geared to identify the specific synaptic molecular substrates of brain aging. Here, we made use of iTRAQ¹ technology and high-coverage mass spectrometry to study the effects of aging on the proteomic composition of mouse hippocampal synaptosomes. We investigated the synaptic proteomes of individual mice at 20, 40, 50, 60, 70, 80, 90, and 100 weeks of age. Our findings show that both specific changes and increased variance in synaptic protein expression are associated with age-related cognitive decline.     

Balancing homeostasis and learning in neural circuits

Neural circuits are remarkably adaptable, providing animals with the ability to modify their behavior on the basis of experience. At the same time, they are extremely robust and maintain stability despite the changes associated with adaptation. This combination of adaptability and stability is difficult to achieve, and it provides a strong constraint on any models of plasticity in neural circuits. New evidence suggests that the effect of action potential timing on synaptic plasticity may be an important element in reconciling homeostasis with adaptability. In particular, spike-timing dependent plasticity can act as both an adaptive and a homeostatic mechanism, controlling overall firing rates and distributions of synaptic efficacies while making neurons selective for certain aspects of their inputs. It can also cause networks that initially represent the present state of a stimulus to predict its future state on the basis of experience, a theoretical result supported by experimental data in behaving rats.     

Reversal of aging‐associated hippocampal synaptic plasticity deficits by reductants via regulation of thiol redox and NMDA receptor function

Deficits in learning and memory accompanied by age‐related neurodegenerative diseases are closely related to the impairment of synaptic plasticity. In this study, we investigated the role of thiol redox status in the modulation of the N‐methyl‐d ‐aspartate receptor (NMDAR)‐dependent long‐term potentiation (LTP) in CA1 areas of hippocampal slices. Our results demonstrated that the impaired LTP induced by aging could be reversed by acute administration of reductants that can regulate thiol redox status directly, such as dithiothreitol or β‐mercaptoethanol, but not by classical anti‐oxidants such as vitamin C or trolox. This repair was mediated by the recruitment of aging‐related deficits in NMDAR function induced by these reductants and was mimicked by glutathione, which can restore the age‐associated alterations in endogenous thiol redox status. Moreover, antioxidant prevented but failed to reverse H₂O₂‐induced impairment of NMDAR‐mediated synaptic plasticity. These results indicate that the restoring of thiol redox status may be a more effective strategy than the scavenging of oxidants in the treatment of pre‐existing oxidative injury in learning and memory.     

Role of sexual and natural selection in evolution of body size and shape: a phylogenetic study of morphological radiation in grouse

We use standardized independent contrasts (SICs) to elucidate the effect of ecology and mating systems on morphological radiation in grouse. The analysis of SICs for 38 skeletal measurements from 20 taxa, showed that changes in mating system had a significant effect on body size of both sexes. Sexual size dimorphism in grouse is consistent with Rensch's rule; the slope of the regression of male vs. female size SICs was 1.4, significantly >1. Changes in habitat were associated with accelerated rates of evolution of body proportions. SICs for male and female scores of size independent factors were directly proportional to each other (slope = 1), indicating extreme similarities between male and female ecology. Females, however, were better adapted to longer, more energy efficient flight than males. Size independent morphological differences among grouse are adaptive and are related to the differences in habitat and foraging behaviour among the species.     

Oxytocin suppresses basal glutamatergic transmission but facilitates activity-dependent synaptic potentiation in the medial prefrontal cortex

Both oxytocin and oxytocin receptors are implicated in neuropsychiatric disorders, particularly autism which involves a severe deficit in social cognition. Consistently, oxytocin enhances social cognition in humans and animals. The infralimbic medial prefrontal cortex (IL-mPFC) is believed to play an important role in the regulation of social cognition which might involve top-down control of subcortical structures including the amygdala. However, little is known about whether and how oxytocin modulates synaptic function in the IL-mPFC. The effect of oxytocin on excitatory neurotransmission in the IL-mPFC was studied by examining both the evoked and spontaneous excitatory neurotransmission in the IL-mPFC layer V pyramidal neurons before and after perfusion with oxytocin. To investigate the effect of oxytocin on synaptic plasticity, low-frequency stimulation-induced long-lasting depression was studied in oxytocin-treated brain slices. Oxytocin produced a significant suppression of glutamatergic neurotransmission in the IL-mPFC layer V pyramidal neurons which was mediated by a reduction in glutamate release. Activation of the cannabinoid CB1 receptors was involved in this pre-synaptic effect. Treatment of brain slices with oxytocin for 1?h converted long-lasting depression into long-lasting potentiation of glutamatergic neurotransmission. This oxytocin-mediated plasticity was NMDA receptor-dependent and was mediated by the synaptic insertion of calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors. The aforementioned suppression of basal glutamatergic neurotransmission and facilitation of activity-dependent synaptic plasticity in the IL-mPFC might be critical for the effect of oxytocin on social cognition.