Involvement of hippocampal synaptic plasticity in age-related memory decline

This article examines the functional significance of Ca²⁺-dependent synaptic plasticity in relation to compromised memory function during aging. Research characterizing an age-related decline in memory for tasks that require proper hippocampal function is summarized. It is concluded that aged animals possess the mechanisms necessary for memory formation, and memory deficits, including rapid forgetting, result from more subtle changes in memory processes for memory storage or maintenance. A review of experimental studies concerning changes in hippocampal neural plasticity over the course of aging indicates that, during aging, there is a shift in mechanisms that regulate the thresholds for synaptic modification, including Ca²⁺ channel function and subsequent Ca²⁺-dependent processes. The results, combined with theoretical considerations concerning synaptic modification thresholds, provide the basis for a model of age-related changes in hippocampal synaptic function. The model is employed as a foundation for interpretation of studies examining therapeutic intervention in age-related memory decline. The possible role of altered synaptic plasticity thresholds in learning and memory deficits suggests that treatments that modify synaptic plasticity may prove fruitful for the development of early therapeutic interventions in age-related neurodegenerative diseases.     

Diet-induced insulin resistance impairs hippocampal synaptic plasticity and cognition in middle-aged rats

Overall dietary energy intake, particularly the consumption of simple sugars such as fructose, has been increasing steadily in Western societies, but the effects of such diets on the brain are poorly understood. Here, we used functional and structural assays to characterize the effects of excessive caloric intake on the hippocampus, a brain region important for learning and memory. Rats fed with a high-fat, high-glucose diet supplemented with high-fructose corn syrup showed alterations in energy and lipid metabolism similar to clinical diabetes, with elevated fasting glucose and increased cholesterol and triglycerides. Rats maintained on this diet for 8 months exhibited impaired spatial learning ability, reduced hippocampal dendritic spine density, and reduced long-term potentiation at Schaffer collateral--CA1 synapses. These changes occurred concurrently with reductions in levels of brain-derived neurotrophic factor in the hippocampus. We conclude that a high-calorie diet reduces hippocampal synaptic plasticity and impairs cognitive function, possibly through BDNF-mediated effects on dendritic spines.     

Impaired hippocampal memory function and synaptic plasticity in experimental cortical dysplasia

Purpose: Memory impairment is a common comorbidity in people with epilepsy‐associated malformations of cortical development. We studied spatial memory performance and hippocampal synaptic plasticity in an animal model of cortical dysplasia. Methods: Embryonic day 17 rats were exposed to 2.25 Gy external radiation. One‐month‐old rats were tested for spatial recognition memory. After behavioral testing, short‐term and long‐term synaptic plasticity in the hippocampal CA1 region was studied in an in vitro slice preparation. Key Findings: Behavioral assessments showed impaired hippocampal CA1‐dependent spatial recognition memory in irradiated rats. Neurophysiologic assessments showed that baseline synaptic transmission was significantly enhanced, whereas paired‐pulse facilitation, long‐term potentiation, and long‐term depression of the field excitatory postsynaptic potential (fEPSP) slope at Schaffer collateral/commissural fiber‐CA1 synapses were significantly reduced in the irradiated rats. Histologic observations showed dysplastic cortex and dispersed hippocampal pyramidal neurons. Significance: This study has shown that prenatally irradiated rats with cortical dysplasia exhibit a severe impairment of spatial recognition memory accompanied by disrupted short‐term and long‐term synaptic plasticity and may help to guide development of potential therapeutic interventions for this important problem.     

Dietary obesity reversibly induces synaptic stripping by microglia and impairs hippocampal plasticity

Obesity increases risk of age-related cognitive decline and is accompanied by peripheral inflammation. Studies in rodent models of obesity have demonstrated that impaired hippocampal function correlates with microglial activation, but the possibility that neuron/microglia interactions might be perturbed in obesity has never been directly examined. The goal of this study was to determine whether high fat diet-induced obesity promotes synaptic stripping by microglia, and whether any potential changes might be reversible by a return to low-fat diet (LFD). Time course experiments revealed that hippocampal inflammatory cytokine induction and loss of synaptic protein expression were detectable after three months of HFD, therefore subsequent groups of mice were maintained on HFD for three months before being switched to LFD for an additional two months on LFD (HFD/LFD). Additional HFD mice continued to receive HFD during this period (HFD/HFD), while another group of mice were maintained on LFD throughout the experiment (LFD/LFD). Dietary obesity impaired hippocampus-dependent memory, reduced long-term potentiation (LTP), and induced expression of the activation marker major histocompatibility complex II (MHCII) in hippocampal microglia. Diet reversal only partially attenuated increases in adiposity in HFD/LFD mice, but plasticity deficits and MHCII induction were normalized to within the range of LFD/LFD mice. Microglial activation and deficits in hippocampal function were accompanied by perturbation of spatial relationships between microglial processes and synaptic puncta. Analysis of primary microglia isolated from HFD/HFD mice revealed selective increases in internalization of synaptosomes labeled with a pH-sensitive fluorophore. Taken together, these findings indicate that dietary obesity reversibly impairs hippocampal function, and that deficits may be attributable to synaptic stripping by microglia.     

Adult hippocampal neurogenesis, synaptic plasticity and memory: facts and hypotheses

The demonstration that progenitor cells in regions of the adult mammalian brain such as the dentate gyrus of the hippocampus can undergo mitosis and generate new cells that differentiate into functionally integrated neurons throughout life has marked a new era in neuroscience. In recent years, a wide range of investigations has been directed at understanding the physiological mechanisms and functional relevance of this form of brain plasticity. Our current knowledge of adult hippocampal neurogenesis indicates that the production of new cells in the brain follows a multi-step process during which newborn cells are submitted to various regulatory factors that influence cell proliferation, maturation, fate determination and survival. As details of the dynamics of morphological maturation and functional integration of newborn neurons in corticohippocampal circuits have become clearer, an increasing number of studies have examined how environmental and/or behavioural factors can modulate neurogenesis and affect hippocampal-dependent learning and memory. In this article we present an overview of recent literature that relates neurogenesis to hippocampal function on the basis of correlative studies investigating the modulation of neurogenesis by learning and behavioural experience, and the consequences of the loss of hippocampal neurogenesis for memory function. We also highlight experimental evidence that immature neurons exhibit unique electrophysiological characteristics and therefore may constitute a specific cell population particularly inclined to undergo activity-dependent plasticity. Moreover, we review recent work that reveals an unsuspected mechanistic link between synaptic plasticity and the proliferation and survival of new hippocampal neurons. From the present background of research, we argue that the incorporation of functional adult-generated neurons into existing neural networks provides a higher capacity for plasticity, which may favour the encoding and storage of certain types of memories. Depending on their birth date and maturation stage, new neurons might be implicated in the encoding/storage process of the task at hand or may help future learning experience. Finally, we highlight critical issues to be addressed in order to decipher the exact contribution of newly generated neurons to cognitive functions.     

ApoE4 impairs hippocampal plasticity isoform-specifically and blocks the environmental stimulation of synaptogenesis and memory

Alzheimer's disease (AD) is associated with genetic risk factors, of which the allele E4 of apolipoprotein E (apoE4) is the most prevalent, and is affected by environmental factors that include education early in life and socioeconomic background. The extent to which environmental factors affect the phenotypic expression of the AD genetic risk factors is not known. Here we show that the neuronal and cognitive stimulations, which are elicited by environmental enrichment at a young age, are markedly affected by the apoE genotype. Accordingly, exposure to an enriched environment of young mice transgenic for human apoE3, which is the benign AD apoE allele, resulted in improved learning and memory, whereas mice transgenic for human apoE4 were unaffected by the enriched environment and their learning and memory were similar to those of the nonenriched apoE3 transgenic mice. These cognitive effects were associated with higher hippocampal levels of the presynaptic protein synaptophysin and of NGF in apoE3 but not apoE4 transgenic mice. In contrast, cortical synaptophysin and NGF levels of the apoE3 and apoE4 transgenic mice were similarly elevated by environmental enrichment. These findings show that apoE4 impairs hippocampal plasticity and isoform-specifically blocks the environmental stimulation of synaptogenesis and memory. This provides a novel mechanism by which environmental factors can modulate the function and phenotypic expression of the apoE genotype.     

Hippocampus as a memory map: synaptic plasticity and memory encoding by hippocampal neurons.

Hippocampal cells contribute to memory by rapidly encoding information about the perceptual and behavioral structure of experience. This paper describes two complementary experimental approaches that illustrate two important mechanisms that confer these properties to hippocampal cells: (1) Enduring spatial memory and stable place fields each depend upon synaptic plasticity mechanisms that normally rely on the same NMDA-receptor mediated metabolic events as long-term potentiation (LTP). Thus, hippocampal cells "learn" to encode information about the perceptual and behavioral structure of experiences. (2) Hippocampal cells encode the structure of experience and respond in a manner inconsistent with a spatial representation. Place fields are distributed heterogeneously in space, their locations are determined by non-geometric information, the population of active cells can indicate more than one location in space, and hippocampal cells encode discriminative stimuli independent of their spatial location. To the extent that the hippocampus encodes a map, it is more simply described as a memory map than a spatial map. Rather than computing spatial locations, the space it encodes is better described as a life or a problem space that encodes the history of experience into the relational structure of episodes.     

Triggers and substrates of hippocampal synaptic plasticity

It is widely assumed that behavioral learning reflects adaptive properties of the neuronal networks underlying behavior. Adaptive properties of networks in turn arise from the existence of biochemical mechanisms that regulate the efficacy of synaptic transmission. Considerable progress has been made in the elucidation of the mechanisms involved in synaptic plasticity at central synapses and especially those responsible for the phenomenon of long-term potentiation (LTP) of synaptic transmission in hippocampus. While the nature and the timing requirements of the triggering steps are reasonably well known, there is still a lot of uncertainty concerning the mechanisms responsible for the long-term changes. Several biochemical processes have been proposed to play critical roles in promoting long-lasting modifications of synaptic efficacy. This review examines first the triggers that are necessary to produce LTP in the hippocampus and then the different biochemical processes that have been considered to participate in the maintenance of LTP. Finally, we examine the relationships between LTP and behavioral learning.     

Parallel nature of hippocampal synaptic plasticity

This study demonstrates that the mechanisms involved in the production of long-term potentiation (LTP) in the hippocampus appear to be independent of those which generate shorter-lasting plasticity, but that both processes are activated concurrently following an LTP-inducing stimulus. Adult male Sprague-Dawley rats were anesthetized using either pentobarbital or secobarbital to record extracellular field potentials from the hippocampal CA1 pyramidal cell layer in response to stimulation of commissural afferents. Plasticity was generated by the delivery of a five-pulse patterned stimulus train, consisting of one priming pulse followed 170 milliseconds later by a burst of four pulses at 200 Hz. While similar LTP was observed in both groups, short-term plasticity was absent in the secobarbital-anesthetized animals. This result suggests that different plasticity mechanisms in the hippocampus are activated in parallel by the triggering stimulus. Synapse 30:112–115, 1998. © 1998 Wiley-Liss, Inc.     

Lipid signaling and synaptic plasticity.

Lipids are essential components of plasma- and organelle-membranes, not only providing a frame for embedded proteins (e.g., receptors and ion channels) but also functioning as reservoirs for lipid mediators. Increasing evidence indicates that bioactive lipids such as eicosanoids, endocannabinoids, and lysophospholipids serve as intercellular and intracellular signaling molecules participating in physiological and pathological functions in the brain. The discovery of some of these lipid receptors and novel lipid signaling mediators has sparked an intense interest in lipidomic neurobiology research. Classic prostaglandins (PGD(2), PGE(2), PGF(2alpha), PGI(2), and TXA(2)), catalyzed by cyclooxygenases (COX), are synthesized from arachidonic acid (AA). Experimental studies demonstrate that prostaglandin E(2) (PGE(2)), mainly derived from the COX-2 reaction, is an important mediator, acting as a retrograde messenger via a presynaptic PGE(2) subtype 2 receptor (EP(2)) in modulation of synaptic events. Novel prostaglandins (prostaglandin glycerol esters and prostaglandin ethanolamides) are COX-2 oxidative metabolites of endogenous cannabinoids (2-arachidonyl glycerol and arachidonyl ethanolamide). Recent evidence suggests that these new types of prostaglandins are likely novel signaling mediators involved in synaptic transmission and plasticity. This means that COX- 2 plays a central role in metabolisms of AA and endocannabinoids (eCBs) and productions of AA- and eCB- derived prostaglandins. Thus, in the present review article, the authors will mainly discuss COX-2 regulation of prostaglandin signaling in modulation of hippocampal synaptic transmission and plasticity.     

Cannabinoids modulate hippocampal memory and plasticity

Considerable evidence demonstrates that cannabinoid agonists impair whereas cannabinoid antagonists improve memory and plasticity. However, recent studies suggest that the effects of cannabinoids on learning do not necessarily follow these simple patterns, particularly when emotional memory processes are involved. We investigated the involvement of the cannabinoid system in hippocampal learning and plasticity using the fear‐related inhibitory avoidance (IA) and the non‐fear‐related spatial learning paradigms, and cellular models of learning and memory, i.e., long‐term potentiation (LTP) and long‐term depression (LTD). We found that microinjection into the CA1 of the CB1/CB2 receptor agonist WIN55,212‐2 (5 μg/side) and an inhibitor of endocannabinoid reuptake and breakdown AM404 (200 ng/side) facilitated the extinction of IA, while the CB1 receptor antagonist AM251 (6 ng/side) impaired it. WIN55,212‐2 and AM251 did not affect IA conditioning, while AM404 enhanced it, probably due to a drug‐induced increase in pain sensitivity. However, in the water maze, systemic or local CA1 injections of AM251, WIN55,212‐2, and AM404 all impaired spatial learning. We also found that i.p. administration of WIN55,212‐2 (0.5 mg/kg), AM404 (10 mg/kg), and AM251 (2 mg/kg) impaired LTP in the Schaffer collateral‐CA1 projection, whereas AM404 facilitated LTD. Our findings suggest diverse effects of the cannabinoid system on CA1 memory and plasticity that cannot be categorized simply into an impairing or an enhancing effect of cannabinoid activation and deactivation, respectively. Moreover, they provide preclinical support for the suggestion that targeting the endocannabinoid system may aid in the treatment of disorders associated with impaired extinction‐like processes, such as post‐traumatic stress disorder. © 2009 Wiley‐Liss, Inc.     

Multideterminant role of calcium in hippocampal synaptic plasticity

Hippocampal CA1 cells possess several varieties of long-lasting synaptic plasticity: two different forms of long-term potentiation (LTP) and at least one form of long-term depression (LTD). All forms of synaptic plasticity are induced by afferent activation, all involve Ca²⁺ influx, all can be blocked by Ca²⁺ chelators, and all activate Ca²⁺-dependent mechanisms. The question arises as how different physiological responses can be initiated by activation of the same second messenger. We consider two hypotheses which could account for these phenomena: voltage-dependent differences in cytosolic Ca²⁺ concentration acting upon Ca²⁺ substrates of differing Ca²⁺ affinities and compartmentalization of the Ca²⁺ and its substrates. © 1994 Wiley-Liss, Inc.     

Neurotrophins and hippocampal synaptic transmission and plasticity.

Neurotrophins are traditionally thought to be secretory proteins that regulate long-term survival and differentiation of neurons. Recent studies have revealed a previously unexpected role for neurotrophins in synaptic development and plasticity in diverse neuronal populations. In this review, we focus on the synaptic function of brain-derived neurotrophic factor (BDNF) in the hippocampus. Although a variety of in vitro experiments have shown the ability of BDNF to acutely modulate synaptic transmission, whether BDNF truly potentiates basal synaptic transmission in hippocampal neurons remains controversial. More consistent evidence has been obtained for the role of BDNF in long-term potentiation (LTP), a cellular model for learning and memory. BDNF also potentiates high frequency transmission by modulating the number of docked vesicles and the levels of the vesicle protein synaptobrevin and synaptophysin at the CA1 synapses. Both pre- and postsynaptic effects of BDNF have been demonstrated. Recent studies have begun to address the role of BDNF in late-phase LTP and in the development of hippocampal circuit. BDNF and other neurotrophins may represent a new class of neuromodulators that regulate neuronal connectivity and synaptic efficacy. J. Neurosci. Res. 58:76-87, 1999. Published 1999 Wiley-Liss, Inc.     

c-Jun N-terminal kinases in memory and synaptic plasticity

The c-Jun N-terminal kinases (JNK) belong to the subfamily of mitogen-activated protein kinases (MAPK). JNK is an important signaling enzyme that is involved in many facets of cellular regulation including gene expression, cell proliferation and programmed cell death. Activation of JNK isoforms (JNK1, 2, and 3) is regarded as a molecular switch in stress signal transduction. The activation of JNK pathways is also critical for pathological death associated with neurodegenerative diseases. Considering that a variety of stressors activate JNK, it is surprising that the role of hippocampal JNK in memory and synaptic plasticity has not yet been systematically investigated. Here we summarize the emerging evidence for the functions of hippocampal JNK in memory and synaptic plasticity, including our recent demon-stration that JNK isoforms play critical roles in regulation of contextual fear conditioning under stressful and baseline conditions. We postulate that sustained activation of the hippocampal JNK2 and JNK3 pathways is involved in the initial stress response that ultimately leads to deficits in memory and long-term potentiation, whereas transient JNK1 activation regulates baseline contextual fear conditioning. Results obtained within the framework of our recent findings will be used for future work, which will differentiate mechanisms underlying beneficial short-term JNK action from prolonged JNK activation that may lead to memory deficits and neurodegeneration.     

Increased EID1 nuclear translocation impairs synaptic plasticity and memory function associated with pathogenesis of Alzheimer's disease

Though loss of function in CBP/p300, a family of CREB-binding proteins, has been causally associated with a variety of human neurological disorders, such as Rubinstein-Taybi syndrome, Huntington's disease and drug addiction, the role of EP300 interacting inhibitor of differentiation 1 (EID1), a CBP/p300 inhibitory protein, in modulating neurological functions remains completely unknown. Through the examination of EID1 expression and cellular distribution, we discovered that there is a significant increase of EID1 nuclear translocation in the cortical neurons of Alzheimer's disease (AD) patient brains compared to that of control brains. To study the potential effects of EID1 on neurological functions associated with learning and memory, we generated a transgenic mouse model with a neuron-specific expression of human EID1 gene in the brain. Overexpression of EID1 led to an increase in its nuclear localization in neurons mimicking that seen in human AD brains. The transgenic mice had a disrupted neurofilament organization and increase of astrogliosis in the cortex and hippocampus. Furthermore, we demonstrated that overexpression of EID1 reduced hippocampal long-term potentiation and impaired spatial learning and memory function in the transgenic mice. Our results indicated that the negative effects of extra nuclear EID1 in transgenic mouse brains are likely due to its inhibitory function on CBP/p300 mediated histone and p53 acetylation, thus affecting the expression of downstream genes involved in the maintenance of neuronal structure and function. Together, our data raise the possibility that alteration of EID1 expression, particularly the increase of EID1 nuclear localization that inhibits CBP/p300 activity in neuronal cells, may play an important role in AD pathogenesis.     

Role of phosphodiesterase 5 in synaptic plasticity and memory

Phosphodiesterases (PDEs) are enzymes that break down the phosphodiesteric bond of the cyclic nucleotides, cAMP and cGMP, second messengers that regulate many biological processes. PDEs participate in the regulation of signal transduction by means of a fine regulation of cyclic nucleotides so that the response to cell stimuli is both specific and activates the correct third messengers. Several PDE inhibitors have been developed and used as therapeutic agents because they increase cyclic nucleotide levels by blocking the PDE function. In particular, sildenafil, an inhibitor of PDE5, has been mainly used in the treatment of erectile dysfunction but is now also utilized against pulmonary hypertension. This review examines the physiological role of PDE5 in synaptic plasticity and memory and the use of PDE5 inhibitors as possible therapeutic agents against disorders of the central nervous system (CNS).     

Impaired interleukin-1 signaling is associated with deficits in hippocampal memory processes and neural plasticity

The cytokine interleukin-1 (IL-1) is produced by peripheral immune cells as well as glia and neurons within the brain; it plays a major role in immune to brain communication and in modulation of neural, neuroendocrine, and behavioral systems during illness. Although previous studies demonstrated that excess levels of IL-1 impaired memory processes and neural plasticity, it has been suggested that physiological levels of IL-1 are involved in hippocampal-dependent memory and long-term potentiation (LTP). To examine this hypothesis, we studied IL-1 receptor type I knockout (IL-1rKO) mice in several paradigms of memory function and hippocampal plasticity. In the spatial version of the water maze test, IL-1rKO mice displayed significantly longer latency to reach a hidden platform, compared with wild-type controls. Furthermore, IL-1rKO exhibited diminished contextual fear conditioning. In contrast, IL-1rKO mice were similar to control animals in hippocampal-independent memory tasks; i.e., their performance in the visually guided task of the water maze and the auditory-cued fear conditioning was normal. Electrophysiologically, anesthetized IL-1rKO mice exhibited enhanced paired-pulse inhibition in response to perforant path stimulation and no LTP in the dentate gyrus. In vitro, decreased paired-pulse responses, as well as a complete absence of LTP, were observed in the CA1 region of hippocampal slices taken from IL-1rKO mice compared with WT controls. These results suggest that IL-1 contributes to the regulation of memory processes as well as short- and long-term plasticity within the hippocampus. These findings have important implications to several conditions in humans, which are associated with long-term defects in IL-1 signaling, such as mutations in the IL-1 receptor accessory protein-like gene, which are involved in a frequent form of X-linked mental retardation.     

Suppression of hippocampal synaptic plasticity during slow-wave sleep

The influence of behavioral state on the induction of long-term enhancement (LTE) of hippocampal synapses was studied in chronically prepared animals. Perforant path evoked field potentials and EEG were recorded from fascia dentata during slow-wave sleep (SWS) and waking. LTE was strongly suppressed during SWS, suggesting that hippocampal information storage may be inactivated at certain phases of the sleep cycle. Normal LTE was observed in the same animals while awake.     

Dorsal hippocampal kindling selectively impairs spatial learning/short-term memory.

Kindling with electrical stimulation of the dorsal hippocampus has been shown to disrupt spatial task performance in rats. The present study investigated the specificity of this effect in terms of the possible contribution of nonmnemonic effects, the presence of a more general mnemonic deficit, and the involvement of learning/short-term memory and/or long-term memory processes. Rats were fully kindled with stimulation of the dorsal hippocampus and subsequently tested for acquisition, 7-day retention, and 28-day retention of a hidden platform (HP) location in the Morris water maze and an object discrimination problem in a modified water maze. To control for nonmnemonic behavioral impairments, testing on both tasks was preceded by training on visible platform control tasks. Kindling impaired acquisition of the HP location but spared performance on all other aspects of testing, indicating a specific impairment of spatial learning/short-term memory. These results suggest that epileptogenesis induced by hippocampal stimulation is indeed associated with a selective disruption of the mechanisms mediating spatial learning/short-term memory.